Intake Food

SYMPOSIUM: DRY MATTER INTAKE OF LACTATING DAIRY CATTLE

Integration of Metabolism and Intake Regulation:A Review Focusing on Periparturient Animals

K. L. Ingvartsen and J. B. AndersenDanish Institute of Agricultural Sciences

Department of Animal Health and WelfareResearch Centre Foulum

P.O. Box 50DK-8830 Tjele, Denmark

ABSTRACT

There has been great interest in dry matter intakeregulation in lactating dairy cattle to enhance perfor-mance and improve animal health and welfare. Pre-dicting voluntary dry matter intake (VDMI) is complexand influenced by numerous factors relating to the diet,management, housing, environment and the animal.The objective of this review is to identify and discussimportant metabolic factors involved in the regulationof VDMI and their integration with metabolism. Wehave described the adaptations of intake and metabo-lism and discussed mechanisms of intake regulation.Furthermore we have reviewed selected metabolic sig-nals involved in intake regulation.

A substantial dip in VDMI is initiated in late preg-nancy and continues into early lactation. This dip hastraditionally been interpreted as caused by physicalconstraints, but this role is most likely overemphasized.The dip in intake coincides with changes in reproduc-tive status, fat mass, and metabolic changes in supportof lactation, and we have described metabolic signalsthat may play an equally important role in intake regu-lation. These signals include nutrients, metabolites, re-productive hormones, stress hormones, leptin, insulin,gut peptides, cytokines, and neuropeptides such as neu-ropeptide Y, galanin, and corticotrophin-releasing fac-tor. The involvement of these signals in the peripartur-ient dip in intake is discussed, and evidence supportingthe integration of the regulation of intake and metabo-lism is presented. Still, much research is needed toclarify the complex regulation of VDMI in lactatingdairy cows, particularly in the periparturient animal.(Key words: intake regulation, metabolism, peripart-urient, peptides)

Received July 28, 1999.Accepted January 10, 2000.Corresponding author: Klaus L. Ingvartsen; e-mail: KlausL.

[email protected].

2000 J Dairy Sci 83:1573–1597 1573

Abbreviation key: APR = acute phase inflammatoryresponse, ARN = arcuate nucleus, BBB = blood-brainbarrier, CCK = cholecystokinin, CNS = central nervoussystem, CRF = corticotrophin-releasing factor, GLP-1= glucagon-like peptide 1, GLP-2 = glucagon-like pep-tide 2, IL = interleukin, IV = intravenous, ICV = intrace-rebroventricular, LH = lateral hypothalamus, LPS =lipopolysaccharide, NPY = neuropeptide Y, PVN =paraventricular nucleus, SS = somatostatin, TNF-α =tumor necrosis factor-α, VDMI = voluntary DMI, VLH= ventrolateral hypothalamus, VMH = ventromedialhypothalamus.

INTRODUCTION

The factors affecting voluntary DMI (VDMI) of lactat-ing dairy cattle have received much attention for manydecades. The traditional motivation for studying factorsaffecting VDMI has been, and still is, the scope forincreasing intake and hence production, efficiency, andprofitability. An alternative motivation for studyingfactors affecting VDMI and feed intake regulation is tobetter understand the role of, and ultimately manipu-late, intake in relation to animal health. Most of thehealth problems in the highly selected dairy cow, ofboth metabolic and infectious nature, occur in earlylactation and have been related to relatively low intakejust prior to parturition (342). Furthermore, infectiousdiseases are also known to down-regulate appetite viacytokines in the immune system (172, 334). To under-stand and possibly prevent hypophagia, we need to bet-ter understand and be able to quantify the linkagesbetween mechanisms of intake regulation, metabolism,and the immune system in the dairy cow.

Numerous models for predicting VDMI have beendeveloped as shown in reviews by Ingvartsen (161) andMertens (225). Critical evaluation of some of the modelscurrently in use indicates that these models are inaccu-rate since they exclude important factors known to in-fluence VDMI (161, 225). In particular, nearly all mod-els are incapable of predicting intake in the peripartur-ient animal (161, 265) and late (> 40 wk) lactation (265).The few recent models developed for periparturient

INGVARTSEN AND ANDERSEN1574

cows (264) are probably not universal since they aredeveloped to fit a certain type of cow and diet. We believethe metabolic component in intake regulation has beenunderemphasized in most previous attempts to developmodels for predicting intake. Original attempts havebeen made by Forbes (112) and Fisher et al. (104) tostudy the interactions between metabolic control andphysical limitations of feed intake in ruminants. How-ever, intake regulation is a very complex biological phe-nomenon. Eating behavior and food intake are the re-sults of neural integration of numerous signals relatingto the environment, feed, and the physiological state ofthe animal. We have some insight into the nature ofthese signals in ruminants (12, 100, 114, 236), but muchstill has to be learned about which factors are involvedin intake regulation and how these factors are inte-grated with the physiological state and metabolism ofthe animal.

More research is needed on intake regulation andhow intake is integrated with metabolism, particularlyin periparturient animals. A better understanding ofintake regulation and its integration with metabolismwill most likely improve concepts on intake regulationand, thereby, the accuracy of models for prediction ofintake, production, and energy balance, and ultimatelymake it possible to further improve animal health andproductivity in the future. Consequently, the objectiveof the present review is to identify and discuss im-portant metabolic factors that may regulate VDMI andtheir integration with metabolism of dairy cattle. Inparticular, we will examine the nature of the dip inintake in periparturient animals.

We do not attempt to give a complete review of thephysiology of intake regulation, but rather to focus onpossible signals involved in the homeorhetic regulationof intake. We have chosen to describe the naturallyoccurring adaptations of intake and metabolism in peri-parturient animals and briefly describe the regulationof the metabolic adaptations. Evidence is given of meta-bolic regulation of intake, the link between body re-serves and intake, and humoral signals involved in in-tegrating appetite and BW to show that metabolic fac-tors are equally important as physical factors inregulating intake. Subsequently, we review the role ofselected signals involved in intake regulation. We havechosen to primarily focus on signals involved in thelong-term regulation of intake and include nutrient,metabolite, hormonal, gut peptide, and cytokine sig-nals. Finally, we briefly discuss central integration ofmetabolism and intake regulation and the role of se-lected neuropeptides. Much of the literature reviewedis on laboratory animals and humans because informa-tion on ruminants is still lacking or limited.

Journal of Dairy Science Vol. 83, No. 7, 2000

Figure 1. The pattern of the transient dip in voluntary dry matterintake around calving in heifers and cows (K. L. Ingvartsen etal., unpublished).

ADAPTATIONS OF INTAKE AND METABOLISM

Patterns of VDMI

Major changes occur in VDMI both within and be-tween lactations in the dairy cow. Figure 1 shows thetransient dip in intake starting in late pregnancy andcontinuing into early lactation. This dip does not justoccur in the last few weeks before calving as suggested,e.g., in the National Research Council recommenda-tions from 1988 (236). Pregnancy in dairy heifers hasbeen shown to reduce VDMI intake from wk 26 of preg-nancy by 1.53% (or approximately 0.17 kg) per weekuntil 3 wk before calving (162). In a more recent study,in which the energy density of the diet remained con-stant during the last 168 d of pregnancy (164), we ob-served a similar decline in energy intake during thelast trimester of pregnancy both in heifers and lactatingcows when diet energy was high (11.6 MJ of metaboliz-able energy/kg of DM), while the decline was muchsmaller or insignificant at lower energy densities (10.2or 8.3 MJ of metabolizable energy/kg of DM) in accor-dance with Coppock (72).

The lowest VDMI occurs at calving. PostpartumVDMI increases, but the rate with which it increasesand to which level vary considerably. In cows givendiets of constant composition, the milk yield typicallypeaks between 5 to 7 wk postpartum, while maximumintake is reached between 8 and 22 wk after calving.The increase in intake from wk 1 postpartum to timeof peak intake has been reported to vary between 2 and111% (34). These differences in intake are affected bythe diet fed during lactation but may also depend onprepartum feeding via, at least in part, the influence

SYMPOSIUM: DRY MATTER INTAKE OF LACTATING DAIRY CATTLE 1575

Table 1. A partial list of metabolic changes associated with onset of lactation in ruminants (23).

Physiological function Metabolic change Tissue involved

Milk synthesis ↑ synthetic capacity Mammary↑ blood flow↑ nutrient uptake and use

Lipid metabolism ↑ lipolysis Adipose↓ lipogenesis↑ use of lipid as energy Other body tissues

Glucose metabolism ↑ gluconeogenesis Liver↓ use of glucose Other body tissues

Protein metabolism ↑ protein mobilization Muscle and other bodytissues

Mineral metabolism ↑ absorption Gut↑ mobilization Bones

Intake ↑ food consumption Central nervous systemDigestion ↑ Hypertrophy of digestive tract Digestive tract (incl. Liver)

↑ capacity for nutrient absorption

↓ : decreasing; ↑ : increasing.

on the degree of fatness or BCS of periparturient ani-mals (45, 124, 163).

Voluntary DMI is considerably higher in multiparouscows compared with primiparous cows as illustratedin Figure 1. The intake capacity of primiparous cowscalving at an age of 2 yr is only around 80% of that ofmultiparous cows in the first part of lactation (170, 188).

The normal pattern of intake may be severely influ-enced by disease states. Both clinical and subclinicalinfections are known to substantially reduce appetiteand performance. On the surface, the occurrence of hy-pophagia due to infectious and noninfectious sub-stances, particularly in the periparturient cow, seemssomewhat paradoxical. Febrile animals not only needenergy to fuel elevated body temperature and nutrientsfor repair of tissue breakdown but hypophagia mayalso lead to metabolic diseases such as fatty liver andketosis, at least in the periparturient dairy cow. How-ever, as pointed out by Hart (143), the behavior of sickanimals is not only maladaptive response, but ratheran organized strategy that facilitates recovery andsurvival.

Adaptation and Patterns of Metabolism

During late pregnancy and lactation, energy require-ments increase considerably. Fetal energy require-ments on d 250 of pregnancy have been calculated to 2.3Mcal/d for Holstein cows (27). During lactation, energyrequirement is increased to 26 Mcal net energy in cowsproducing 30 kg of milk per day (27). Major changes inmetabolism occur to cope with this increase in nutrientrequirements (Table 1) and comprehensive reviews onthis topic exist (23, 27, 223, 327). The changes outlinedin Table 1 certainly indicate that lactation is not just


a function of the mammary gland but involves manyphysiological processes and body tissues.

Our focus will be on lipid and carbohydrate metabo-lism. On a diet high in energy density, pregnant heiferswill have a relatively high plasma concentration of glu-cose and a relatively low concentration of NEFA (Figure2). Postpartum, the concentration of NEFA is highwhile glucose is reduced. These changes reflect the largeneed for glucose and nutrients by the mammary glandand that dairy cows increase the use of lipid as a sourceof energy to support lactation as discussed by Baumanand Currie 20 yr ago (23). The specific time-course ofchanges in the plasma concentration depends on themetabolite in question but is usually initiated in latepregnancy and amplified in early lactation. The NEFAstarts to rise 2 to 3 wk before calving and peaks at

Figure 2. Peripartum changes in the plasma concentration ofglucose and nonesterified fatty acids in heifers (K. L. Ingvartsen etal., unpublished).


Table 2. Changes in some homeorhetic and homeostatic hormones, tissue sensitivity, and responsivenessand effect in selected tissues in pregnancy and lactation.

LactogenesisMid-pregnancy Late pregnancy Early lactation

Potential homeorhetic hormones1

Progesterone ↑ (↓ ) ↓Placental lactogen ↑ ↓Estrogens ↑ ↓Prolactin - (↓ ) ↑Somatotropin - (↓ ) ↑Leptin ? ? ?

Homeostatic hormones1

Insulin ↑ ↓Glucagon - - -CCK and somatostatin ? ? ?

Tissue sensitivityInsulin ↑ ↓ ↓Catecolamines ↑ ↑

Tissue responsivenessInsulin ↓ ↓Catecolamines ↓ ↑ ↑

Liver2

Gluconeogenesis ↑Ketogenesis ↑

Adipose tissue2

Lipogenesis ↑ ↓ ↓FA esterification ↑ ↓ ↓Lipolysis ↑ ↑Glucose utilization ↓ ↓

Skeletal muscle2

Protein synthesis ↓ ↓Protein degradation ↑ ↑Glucose utilization ↓ ↓

↓ : decreasing; ↑ : increasing; ?: unknown in ruminants; -: no significant changes.1Plasma hormone concentration changes.2Changes in rate of metabolic processes.

calving or during the first week of lactation. Glucoseincreases during the last week before calving and dropsabruptly postpartum to reach a minimum 1 to 3 wkinto lactation. Postpartum changes in the plasma con-centration of BHBA are generally opposite those ofglucose.

Regulation of Metabolic Adaptations inPeriparturient Animals

The endocrine system is playing a pivotal role, butthe nervous system and the immune system are alsoinvolved in the regulation of metabolism and nutrientpartitioning. Bauman and Currie (23) applied the con-cept of homeorhesis to the regulation of nutrient parti-tioning in lactation and defined homeorhesis as “theorchestrated or coordinated changes in the metabolismof body tissues necessary to support a physiologicalstate.” In Table 2, an outline of changes in homeorhetichormones and their assumed consequences on tissuesensitivity and responsiveness is presented for differentphysiological states. The reader is referred to recent


reviews for further details on the regulation of meta-bolic adaptations to lactation (23, 27, 28, 327).

The time-course of changes of the different homeor-hetic hormones in periparturient cattle varies consider-ably as shown in Figures 3 and 4. Tucker (318) hasshown that plasma concentrations of sex hormones, glu-cocorticoids, as well as other hormones, change in arelatively narrow time period around parturition. Ap-proximately 5 d before parturition, major increases oc-cur in the plasma concentrations of estrogen and corti-sol. Estrogen and cortisol have their highest concentra-tion at 3 and 0 d before parturition, respectively, afterwhich the concentrations decrease to their normal post-partum levels within few days. In Figure 4, changes insomatotropin and insulin are shown to illustrate thenegative correlation between a homeorhetic hormone(somatotropin) and a homeostatic hormone (insulin).Clearly, a number of hormones are potentially involvedin the adaptation of metabolism and some of these arealso, directly or indirectly, involved in the majorchanges in intake, as will be discussed in later sections.


Figure 3. Changes in the serum concentration of putative ho-meorhetic hormones in cows during the transition period (318).

MECHANISMS OF INTAKE REGULATION

The Dip in Intake in Periparturient Animals

What are the factors that induce the dip in intake inthe periparturient animals? Several mechanisms maybe involved in the dip during the peripartum period.Some have suggested that the dip in intake is caused bythe physical compression of the rumen from the growinguterus or that sex hormones are involved. The physicalcompression of the rumen by the growing uterus andthe increasing amount of abdominal fat have been illus-trated in cows (191) and sheep (109). Makela (212) hasreported a negative relationship between the volumeof abdominal fat and the volume of rumen contents innonlactating dairy cows. In sheep, Forbes (110) foundthe volume of incompressible abdominal content

Figure 4. The serum concentration of growth hormone (GH) andinsulin during the periparturient period in heifers fed similar dietsprepartum and postpartum (Ingvartsen et al., unpublished).


(uterus and abdominal fat) to be inversely related torumen volume at slaughter. Furthermore, he found therumen volume at slaughter positively related to intakeduring the last 2 wk before slaughter in pregnant ewesfed hay. However, the decrease in intake due to de-creased rumen volume is compensated in sheep, at leastin part, by an increase in rate of passage of particlesout of the reticulorumen (66, 137, 175), and it is unlikelythat the decrease in rumen volume should be the solereason for the dip in intake. This is in accordance withCoppock et al. (71) who observed that the decline inVDMI in late pregnancy in cows was more pronouncedwhen the diet contained a high rather than a low pro-portion of concentrate. It is therefore likely that factorsother than physical compression due to the enlargedgravid uterus are involved in the dip in intake in latepregnancy (72). It is furthermore important to realizethat the effects of physical compression coincide withchanges in endocrine factors and body reserves, medi-ated in response to the advancing pregnancy and forth-coming lactation.

At parturition the abdominal cavity is relieved of theamniotic fluid, the fetus, and fetal membranes equiva-lent to a mass of approximately 70 kg in a Holstein cow.The disappearance of such a mass from the abdominalcavity should allow a rapid increase in the VDMI ofphysically limiting feeds in the first few days after calv-ing if the major regulatory mechanism causing the dipin intake around parturition was due to physical com-pression of the rumen volume. In general, however, norapid increase in VDMI is observed after calving, ratherthe increase is relatively slow, at least in relation tothe increase observed in milk yield, as shown by, e.g.,Friggens et al. (120).

As further information has become available, it be-comes clear that to some extent the role of physicalconstraints has been overemphasized in ruminants andthat metabolic and endocrine changes in late pregnancyand early lactation also play a substantial role in thisdip in VDMI (115, 166). This is not unique for rumi-nants. The dip in intake also occurs in rats offereda nutritious diet (298), even though they were eatingsubstantially less than what would be expected as theirphysical capacity (246).

Evidence for Metabolic Regulation of Intake

Both treatments with bST and experiments wherepostruminal infusions of nutrients have been appliedindicate that metabolism or metabolic factors play animportant role in intake regulation. Administration ofexogenous bST has been shown to enhance lactationalperformance and subsequently voluntary feed intake.Bauman et al. (24) demonstrated major increases (23


Figure 5. The pattern of average daily food intake in rats offereda diet high in nutrient density in pregnancy and lactation (298).

to 41%) in milk yield and a subsequent increase inVDMI when dairy cows were treated with varying dailydoses of bST. Since then several studies, particularlystudies using prolonged-release formulations, have con-firmed the increased milk yield, which is typically about10 to 15% (22, 47, 58, 95). The general pattern of re-sponse in milk yield is a rapid increase over the firstfew days, rising to a maximum usually within the firstweek of treatment. Voluntary feed intake does not in-crease until several weeks after the increase in milkyield has occurred (22, 58). The increase in intake de-pends not only on the increase in milk yield but is alsoinfluenced by the quality or density of the diet (58). Theabove findings indicate that energy requirements formilk production are “pulling” VDMI up and that intakeregulation therefore is influenced by metabolism. How-ever, physical limitations clearly also play a role, andgood nutrition and management are prerequisites forimproved performance (22).

Other examples showing that metabolic factors in-fluence VDMI via postruminal mechanisms may befound in experiments using abomasal or duodenal infu-sions of nutrients. Abomasal infusions of fat have re-duced VDMI in some trials or treatments (41, 60, 61,64, 122) but not all (41, 64, 86, 123, 238). The intakeresponse depends on the amount of fat infused but otherfactors such as degree of saturation and the fatty acidchain length may also influence intake. The mecha-nisms involved in the depression of VDMI caused byfat infusion have been little investigated in cattle, butgastrointestinal hormones (62, 242) and fatty acid oxi-dation (276) are reported to be involved and will bediscussed later.


Body Reserves and Voluntary Intake

Voluntary DMI in ruminants is negatively correlatedwith body reserves at a given physiological state. Bineset al. (36) and Bines and Morant (35) studied the effectof body fatness on the food intake of nonlactating cowsin a changeover design. They fed cows to become fat orthin and compared ad libitum intake of straw, hay, andconcentrates. No difference was seen in straw intake,but daily intake of hay and concentrate was reducedby approximately 23%, when cows were fat comparedto thin. They suggested that there was a more rapidutilization of lipogenic substrates by thin cows than byfat cows and this would prevent the excessive accumula-tion in the blood of lipogenic precursors and therebyenhance their absorption from the rumen and stimulatefeed intake in thin cows. The only difference betweenfat and thin cows in rumen and blood metabolites thateven approached significance (P < 0.1) was a lower pro-pionate and a higher glucose postfeeding in the fatcows (35).

Prepartum feeding level may influence the amount ofenergy reserves or BCS and thereby peripartum healthand postpartum performance (44, 124, 133, 163). In-gvartsen et al. (163) reviewed the effect of prepartumfeeding and weight gain on peripartum metabolism andfeed intake based on 24 studies (6 in heifers, 10 in drycows, and 8 in cows in late lactation and the dry period).They argued that the inconsistent postpartum re-sponses to prepartum treatments could be explained,at least in part, by the large differences in prepartuminitial BW and BW gain between treatments. They ob-served a positive relationship between prepartumweight gain and the extent of postpartum mobilizationof body tissues and argued that differences in prepar-tum feeding causing excessive mobilization, more thanapproximately 40 kg of BW, appeared to depress feedintake.

Increased fatness or body reserves also down-regu-lates VDMI in sheep (108, 324). If lean adult sheep arefed a high-energy diet ad libitum they gain weight untilthey weigh approximately twice their initial weight andthey reduce intake during the latter part of the fat-tening period (216, 324). Fat sheep at their static BWreduced energy intake per kilogram of BW to a levelsimilar to that of thin control ewes fed a maintainingdiet (216, 324). Carcass fat increased from between 9and 25% to between 35 and 49% (216, 324). This indi-cates that sheep try to reach certain body fatness andmaintain this body fatness by adjusting intake. Follow-ing a period of force feeding, rats adjusted voluntaryintake to return to the BW prior to the imposed feeding(87). The above clearly indicates that the regulationof body reserves and food intake is coordinated and


supports the lipostatic theory for appetite regulationproposed by Kennedy in 1953 (180). Coincident withthe changes in food intake and body stores, plasmaconcentrations of insulin, thyroid hormones, and NEFAoccurred (216). During the first phases of fattening, alinear increase in plasma insulin concentration oc-curred until around 20 to 25 wk of fattening. Thereafterplasma insulin concentration seemed to increase rap-idly to a sustained very high concentration of around249 pM (216, 324). Furthermore, these changes werecoincidental with a substantial increase in mean fatcell weight that occurred after 20 to 24 wk of fattening(324). However, the above relations do not provide proofof a humoral link between the adipose tissue and appe-tite nor of the signals involved.

Evidence of Humoral Signals CoordinatingAppetite and Body Reserves

Parabiosis is the union of two living individuals. Thisunion may occur spontaneously as in joined twins ormay be produced in experimental animals by surgicaltechniques. The parabiosis technique has been used todemonstrate the involvement of circulating factors orhormones in the regulation of physiological systems(103) and, consequently, whether or not humoral sig-nals are involved in coordinating BW and intake. Her-vey (148) was the first to report that obesity inducedby lesion of the ventromedial hypothalamus (VMH) inone member of a parabiotic rat pair led to hypophagiaand weight loss in the unlesioned rat, results that havebeen confirmed by Nishizawa and Bray (237). WhenParameswaran et al. (243) instead stimulated the lat-eral hypothalamus (LH) of one parabiotic rat electri-cally to obtain a marked increase in intake and weight,the unstimulated parabiont ate progressively less andbecame increasingly thin in accordance with the find-ings of Hervey (148). At death the stimulated parabionthad a major increase in the adipose tissue mass, whilethe unstimulated rat was essentially devoid of fat. Ga-vage overfeeding of one parabiotic rat to induce obesitylikewise caused hypophagia and loss of weight and bodyfat in its partner (140, 237). Reversal of the hypophagiaby tube-feeding the lean parabiont with 100% of theenergy intake of the control rats prevented the loss ofBW and, when gavage overfeeding was stopped, bothanimals returned to normal BW (141). Circulating con-centrations of insulin, glucagon, somatotropin, cortico-sterone, glucose, NEFA, and BHBA (140, 243) were notable to explain the observed changes in intake and lossof weight. These experiments indicated that an un-known humoral satiety factor was acting and was re-lated to elevated body fatness.


There appears to be a genetic basis for this factor aslean mice in parabiosis with genetically obese (db/db)mice quickly lost interest in food and rapidly lost weightand died of apparent starvation (68). Furthermore,weight gain was markedly depressed in obese ob/obmice by parabiosis with lean littermates (67). Coleman(67) observed that obese mice ate less when paired withlean mice compared with other obese mice. He further-more observed that when obese ob/ob mice were pairedwith obese db/db mice they experienced hypophagia andfat loss and had a poor survival rate. The above resultsformed the basis of work which shows that obesity inanimals can occur with a deficiency of an adipose tissue-related satiety factor (ob/ob) or a deficiency in its recep-tor (db/db). We now know that the factor alluded to byKennedy’s lipostatic theory (180) is the hormone leptinthat will be discussed in detail in a later section.

NUTRIENTS AND METABOLITES AS SIGNALSIN INTAKE REGULATION

We have so far discussed aspects of adaptations ofintake and given evidence for the involvement of hor-monal and metabolic factors in intake regulation. Inthe following we will review the involvement of selectedhormonal and metabolic signals in the homeorhetic reg-ulation of intake.

There are numerous nutrients and metabolites thatcould potentially be considered if we were to discussaspects of satiety in relation to meal patterns. In theirpaper, Koopmans et al. (184) have substantiated therole of endogenous signals from the gut or absorbednutrients and their metabolic consequences in intakeregulation. Studies with intravenous (IV) infusion ofnutrients indicate that rats are able to sense plasmanutrients and that they will reduce intake, at leastpartially (239). The sensing system responds to differ-ent nutrients with different degrees of behavioral com-pensation, suggesting that each of the plasma nutrientshas its own sensing system. Because our focus is onthe long-term rather than the short-term regulation ofintake, and is furthermore focused on the peripartur-ient animal, we will limit this discussion to fat mobi-lized from adipose tissue.

Oxidation of Metabolic Fuels

As discussed in previous sections, large amounts ofadipose tissue are mobilized during late pregnancy andearly lactation in support of lactation, causing a rise inthe circulating concentrations and use of NEFA, glyc-erol, and ketone bodies. During this period, a negativerelationship between the plasma concentration ofNEFA and VDMI is observed in cattle (133, 165). In


rats recovering from insulin-induced obesity, negativecorrelations were observed between food intake andplasma levels of NEFA, glycerol, and ketone bodies (52).Therefore, it is reasonable to speculate that NEFA, glyc-erol, and ketone bodies act as potential signals in intakeregulation and that they may play a role in the dip inintake in the periparturient animal.

NEFA. Continuous long-term intravenous infusionof long-chain fatty acids has been shown to cause hypo-phagia in rats (51) and in adult sheep (325). In dairycows, a short-term (4 h) intravenous intralipid infusionresulted in a slightly reduced DM intake in two trials(16). The infusion provided 16.7 MJ of NEL, but themean decrease in intake in the two experiments wasonly 3.8 and 7.1 MJ of NEL.

Fatty acid oxidation in the brain and the liver hasbeen suggested as signals in intake regulation. Kasseret al. (176) suggested that changes in fatty acid utiliza-tion in the ventral hypothalamus reflected changes inthe peripheral energy balance. They found that changesin the rate of fatty acid oxidation in the ventrolateralhypothalamus (VLH) are inversely proportional tochanges in peripheral fat storage and, therefore, mayparticipate in feeding responses to changes in periph-eral fat stores (177, 178). However, testing this hypothe-sis by inducing chronic (14 d) changes in VLH fattyacid oxidation caused no effect on food intake, BW, andplasma glucose, insulin, and NEFA (30). It is thereforeunlikely that fatty acid oxidation in the VLH changesfood intake or peripheral metabolism.

The β-oxidation of fatty acids may be inhibited bymercaptoacetate, which depresses long-chain acyl-CoAdehydrogenase activity (21) or methyl palmoxirate,which depresses the mitochondrial carnitine palmitoyl-transferase I concentration (320). Inhibiting fatty acidoxidation with intraperitoneal injections of mercap-toacetate (276, 292) or methyl palmoxirate (119, 153)increased cumulative food intake in rats but only whenthe rate of fatty acid oxidation was relatively high (276,291). Interestingly, the feeding response to mercap-toacetate is lower in S5B/PL rats that are resistant todietary fat-induced obesity, compared with sensitiveOsborne-Mendel rats (293). The hypophagia is mostlikely mediated by hepatic receptors, because the feed-ing response in rats fed a high fat diet to an inhibitionof fatty acid oxidation by mercaptoacetate diet was par-tially blocked by hepatic branch vagotomy (198). Thehypophagia is probably linked to mitochondrial oxida-tion of NEFA providing satiety signals mediated byvagal afferents (277). Satiety may be caused by mito-chondrial oxidation of fatty acids that may affect thehepatocyte membrane potential through cytosolic ATPand Na-pump activity (193). This theory is supportedby the finding that methyl palmoxirate-induced in-


creases in food intake were negatively related to liverATP content, ATP-to-ADP ratio, and phosphorylationpotential, indicating that a decrease in fatty acid oxida-tion can stimulate feeding behavior by reducing hepaticenergy production (118).

Choi et al. (63) tested the hypothesis that inhibitionof fatty acid oxidation by sodium mercaptoacetateblocks the decrease in feed intake by dairy heifers whenthe fat content of their diet is increased. Instead of theexpected increase in VDMI, they observed a substantialdecrease in intake during the first 4 h postinjection.The reason for the depressed VDMI remains unex-plained but may relate to mercaptoacetate-inducedchanges in hormones and metabolite changes (63, 322).More research is needed to clarify the role of β-oxidationof fatty acids in feed intake regulation and the lowintake of the periparturient cow with high lipid mobili-zation.

Glycerol. The effect of glycerol on intake in rats hasrecently been reviewed (278). Glycerol may influencefeeding through a central nervous system (CNS) mech-anism since intracerebroventricular infusions of glyc-erol in rats have been shown to suppress feeding (78).Subcutaneous administration of low levels of glycerolto rats, however, has given variable results and onlydoses of glycerol increasing plasma glycerol to nonphys-iological levels reliably reduce food intake (51, 105,259). Glycerol infused into the portal vein of castratedmale sheep at a rate of 0.3 mmol min−1 for 3 h did notincrease the peripheral concentration of glycerol andhad no short-term effect on intake (114). Glycerol doesnot seem to be a strong candidate for a signal mediatingreduced intake in periparturient cattle.

Ketone bodies. Increased mobilization of body tis-sues in early lactation is generally associated with anincreased production and concentration of ketones. Inrats, subcutaneous injections of BHBA have beenshown to cause hypophagia (105), whereas its metabolicproduct, acetoacetate did not (196). Because section ofthe hepatic vagus branch eliminated the hypophagiafollowing subcutaneous injections of BHBA (194, 195),it seems reasonable to assume that the liver is involved(278). However, Stricker et al. (307), who also postu-lated a peripheral effect of BHBA on satiety, did notbelieve in a hepatic effect since the liver cannot oxidizeBHBA beyond acetoacetate. Possibly BHBA may affectintake via central mechanisms since chronic intracere-broventricular (ICV) infusion reduces intake in rats(8). Recently, Sun et al. (309) found that chronic (28 d)ICV infusions of BHBA reduced BW gain but not foodintake. The physiological role of BHBA in intake regula-tion is still not clear.


Table 3. Hormones and peptides that increase or to decrease feed intake (3, 39, 173, 267, 272, 335, 337,340).

Increase intake Decrease intake

β-Endorphin Agouti-related protein InsulinDynorphin Anorectin LeptinGalanin Amylin NeurotensinGrowth hormone-releasing hormone Bombesin Norepinephrine (β)Neuropeptide Y Caerulin OxytocinNorepinephrine (α2) CCK 8 and 33 SatietinMelanin-concentrating hormone Corticotropin-releasing factor SerotoninMelanocyte stimulating hormone α Cyclo-His-Pro SomatostatinOpoids Dopamine Substance POrexin A and Orexin B Enterostatin Thyrotropin-Progesterone Estrogen Releasing hormonePeptide YY Gastrin-releasing peptide Vasopressin

Glucagon XeninGlucagon-like peptide-1

HORMONAL SIGNALS IN INTAKE REGULATION

As outlined in previous sections, the reproductivehormones, stress hormones, leptin, hormones involvedin nutrient partitioning, and gut peptides are all poten-tially involved in the regulation of intake. The lengthof the list of potential regulatory hormones or peptideshas increased rapidly in the last 25 yr. A large numberof these hormones or peptides have been shown to playa role in the regulation of intake (Table 3). Clearly, itis beyond our scope to review all of the hormones andpeptides listed in Table 3. We will focus on the reproduc-tive hormones, hormones of the stress-axis, leptin, andinsulin that we believe are involved in the regulationof intake in periparturient animals as previously dis-cussed. Furthermore, we will briefly summarize theinformation on the gut peptides glucagon, glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and so-matostatin (SS). For most of the other hormones orpeptides mentioned in Table 3, limited information isavailable for ruminants.

Reproductive Hormones

Reproductive hormones play an important role in theregulation of appetite and energy metabolism in rats(331) and ruminants (114). Ovariectomy in rats re-sulted in a transient increase in intake for 3 to 4 wkand a sustained elevation of BW (229, 314). The effectsof ovariectomy were reversed by replacement therapywith physiological doses of estrogen—a transient hypo-phagia and a sustained reduction of BW were observedas long as the estrogen treatment continued (229, 314).In general, progesterone reverses nearly all effects ofestrogen on energy balance, including an increase infeed intake (266, 329). The reason for the transienteffect of ovariectomy on intake is not clear but may, atleast in part, be due to simultaneous changes in the


degree of fatness and concurrent changes in leptin con-centration.

Intravenous infusion of 17β-estradiol in amountssimilar to those secreted at estrus and in late pregnancycaused a dose-dependent decrease in food intake in cas-trated male sheep and in goats (113). In cows, intrave-nous injections of 17β-estradiol decreased both milkyield and feed intake (134). Intraventricular injectionsof estradiol-benzoate in castrated male sheep increasedintake at low doses but depressed intake at doses higherthan 60 µg (111), but this may be above the physiologi-cal range. Studies in rats also indicate that the effectof estrogen on food intake is due, at least in part, todirect actions in the brain. The paraventricular nucleus(PVN) of the hypothalamus rather than the ventrome-dial hypothalamus (VMH) is the principal site of actionfor estrogen on food intake (48). Progesterone has notbeen reported to have a direct effect on intake but hasbeen reported to block the effects of estrogen both insheep (111) and in cows (233).

Stress Hormones

Acute stress reactions are coordinated and regulatedby the CNS, partly via increased secretion of hormonesof which corticotrophin-releasing factor (CRF) plays acentral role. The CRF is secreted in the brain, primarilyfrom the PVN of the hypothalamus that has also beenshown to mediate an effect on feeding (187). The CRFhas also been located in the gastrointestinal tract (247).CRF decreases food intake by central mechanisms. Cen-trally administered, CRF reduces feed intake in rodents(9, 154, 261), monkeys (129), and cattle (268). Krahnet al. (186) demonstrated a blocking of stress-inducedhypophagia and partial reversal of CRF-induced satietyafter central administration of a CRF antagonist. Be-cause CRF released into the pituitary portal system


stimulates ACTH, and consequently cortisol, these hor-mones could mediate the decreased appetite. However,hypophysectomy has no effect on feeding or on the ac-tions of CRF on feeding (202, 231). This agrees withthe finding that exogenous cortisol administration doesnot influence intake in sheep (11) and cattle (146). Ifwe assume that the increased cortisol around calving(318) is mediated primarily by CRF and ACTH, thenCRF may play a role in the dip in intake around parturi-tion. Because the concentration of cortisol is reducedto normal postpartum levels within few days of parturi-tion, it is unlikely that CRF plays any major role inintake regulation beyond this time in early lactationunless the animal is stressed.

Leptin

Recently, positional cloning has been used to success-fully identify the ob gene (344) and its receptor (313),the db gene (56), in mice. The product secreted by the obgene was named leptin (from the Greek ‘leptos’ meaningthin) and was isolated in 1994 by Zhang et al. (344).Since the cloning of the gene for leptin and its receptorin mice, the gene has also been cloned in the bovine(171), the pig (31, 260), and chicken (312).

Leptin and its receptor. Leptin is produced primar-ily by adipose cells (210, 215). It circulates both free ofand bound to leptin-binding proteins in rodents andhumans (157, 294). No difference is evident in the pro-portion of free or bound leptin either pre- or postpartumor between normal and insulin-dependent diabetic sub-jects (204). The leptin-binding proteins have not yetbeen characterized in farm animals. Plasma leptinshows a circadian rhythm (296) and appears to have apulsatile secretion (297). Following the identificationof the leptin receptor (Ob-R) by Tartaglia et al. (313),several isoforms have been located. The long isoform,Ob-Rl, is expressed at higher levels in the hypothala-mus and at a lower level in other tissues, while shortisoforms (Ob-Rs) are found in almost all tissues (128,201).

Leptin concentration is affected by body re-serves, BW changes and pregnancy. The plasma lep-tin concentration is positively correlated with body re-serves in rodents (117, 245) and man (50, 70, 211).A diet-induced weight loss causes the plasma leptinconcentration to be markedly reduced in humans androdents (70, 89, 211). A weight gain in humans due tooverfeeding is associated with increased basal leptinconcentrations (211) as much as 300% (181). The levelof plasma leptin drops markedly (approximately 70%)with short-term fasting (24 h) (38, 183) and is, therefore,not solely affected by body fatness. During fasting,plasma leptin concentrations are positively correlated


with glucose and insulin concentrations, while therewas no significant relationship between leptin andBHBA concentrations (38). Fasting under euglycemicconditions did not cause changes in leptin concentra-tions during a 72-h fast (181).

Leptin levels in rats are increased 1.8-fold duringpregnancy, followed by a decrease just before parturi-tion (57, 179). Leptin receptor mRNA levels in theuterus also increase about 2.7-fold during pregnancy,whereas no changes were observed in other tissues (57).Chien et al. (57) suggest that, apart from having effectson appetite, leptin may be involved in the partitioningof nutrients from the mother to the fetus. In humans,Schubring et al. (281) observed that leptin levels in-creased continuously during pregnancy and reached amaximum at 38 to 40 wk. At birth, leptin concentrationsdid not change significantly (25.8 to 23.5 ng/ml) but 3d after delivery, a dramatic decrease in leptin levels to10.6 ng/ml was observed. Six weeks after delivery, lep-tin levels were comparable to the values measured atthe beginning of pregnancy. Other studies have re-ported similar changes in pregnancy or around parturi-tion in humans (310) and rats (4, 179). Terada (316)observed no increase in leptin during pregnancy butobserved a much lower leptin concentration in lactatingcompared with nonlactating rats. The increase in theplasma leptin concentration in early pregnancy, beforeany major changes in body fat and resting metabolicrate, suggests that pregnancy represents a leptin-resis-tant state (149). Leptin levels during pregnancy did notcorrelate with maternal sex steroids (281), but humanchorionic gonadotropin and estrogen significantly in-crease leptin secretion by cultures of 3T3-L1 adipocytes.In early lactation, plasma leptin concentration is re-duced to levels observed in virgin control rats (57, 248)which may contribute to the increase in intake in earlylactation. Pickavance et al. (248) observed that the linkbetween nocturnal food intake and increased serumleptin was broken during lactation and speculated thatthe hypoleptinemia may be an important factor promot-ing the hyperphagia of lactation.

Plasma concentrations of leptin are influenced by anumber of hormones (69, 295). Cortisol within the phys-iological range increases plasma leptin concentrationsubstantially in humans (91, 182). Insulin increasesthe ob-gene expression in rats (273), but short-term(<6 h) or acute hyperinsulinemia does not affect leptinconcentration (76, 183). However, long-term (64 to 72h) increases in insulin, using a hyperinsulinemic eugly-cemic clamp technique, have been shown to increaseboth the peripheral and portal concentration of leptinin rats by up to 50% (183, 185). The basal concentrationsof leptin and IGF-I are not correlated but chronic ad-


ministration of recombinant IGF-I causes a sustaineddecrease in leptin levels in humans (77).

Food intake. Daily intraperitoneal injections of re-combinant leptin reduce food intake and BW and in-crease energy expenditure in ob/ob mice (18, 138, 244,245). In parabiotic studies with mice, recombinant lep-tin has been shown to cross between animals (142) andto reduce food intake, serum glucose and insulin, andBW in ob/ob partners of db/db mice (139). Using genetherapy to induce hyperleptinemia (6- to 10-fold in-crease in plasma) in normal mice caused a 30 to 50%decrease in food intake. These mice gained only 22 g,while control animals gained 124 g during the 24-dexperimental period (56). The site of action at whichleptin exerts its major effect is the hypothalamus. In-deed, ICV injections of leptin cause a rapid decrease inintake and body reserves in ob/ob mice (49, 228, 306),rats (75, 107, 269, 285, 288, 289), and monkeys (311).In the rat, the arcuate nucleus (ARN) appears to bedecisive in controlling appetite (275). However, theVMH also seems to be involved in leptin-induced hypo-phagia since VMH lesions caused hyperphagia despitevery high leptin concentrations (275). Recently, evi-dence for leptin regulation of food intake in humanshas been given (200). In pigs, ICV injections of porcineleptin decreased intake substantially and in a dose-dependent manner (14). Barb et al. (14) found that lep-tin modulates growth hormone secretion—leptin in-creased growth hormone when it was given in supra-physiological levels, but reduced growth hormone re-sponse to growth-hormone releasing factor. Serum IGF-I, insulin, thyroxin, glucose, and NEFA were unaffectedby leptin treatment.

Ruminants. Little is known about the biology of lep-tin in ruminants. In sheep, leptin primarily binds tothe dorso- and ventromedial nuclei of the hypothalamusand to the ARN (90). In ovariectomized ewes, ICV ad-ministration of recombinant human leptin over 3 d de-creased the VDMI significantly (147). Long-term (24 h)but not short-term (0.5 h) incubations of ovine anteriorpituitary tissue with leptin caused an increase ingrowth hormone secretion but reduced the response togrowth hormone-releasing factor (263), which agreeswith results in pigs (14). Leptin treatment elevatedplasma NEFA and lactate but did not affect glucoseor insulin levels, indicating a state of negative energybalance (147). Chilliard et al. (59) cite French studiesthat show a positive correlation between body fatnessand plasma leptin in sheep and cattle. Further, theyreport plasma immunoreactive leptin concentrations insheep and cattle and adipose leptin mRNA in sheepto be decreased by undernutrition and increased byoverfeeding as in rodents and humans.


Based on data from rodents and humans, plasmaleptin concentration is expected to increase in dairycows during the concurrent fattening that usually oc-curs during pregnancy. In contrast, plasma leptin con-centration is expected to decrease in the immediateprepartum period and early lactation when dairy cowsmobilize adipose tissue in support of lactation. Thisfall in leptin should be associated with an enhancedappetite. In the immediate prepartum period, such anincreased appetite does not occur, perhaps because in-take in this period is affected significantly by otherfactors. A reduced leptin concentration in early lacta-tion is potentially involved in intake regulation in earlylactation but clearly more research in cattle is needed.

Insulin

The short-term effects of insulin on satiety in rumi-nants have recently been reviewed by Grovum (132),who focused on its relationship with short chain fattyacids and post-prandial release. Thus, we will focuson the role of insulin as a signal of energy status tothe brain.

Insulin clearly exerts biological effects on brain tis-sue. Insulin acts as a neuromodulator within the ner-vous system (19, 20), and has been implicated in theautonomic function (271) and the growth and develop-ment of the CNS (20). Twenty-five years ago, insulinwas actually the first peptide shown to be able to de-crease intake when injected short-term into the intra-ventromedial hypothalamus of rats (144). Since then,insulin has been shown to be involved in the centralregulation of both food intake and BW (258). Woods etal. (339) suggested that insulin might be a sensor ofthe peripheral metabolic status in monogastrics. Thistheory is supported by the positive correlation betweenplasma insulin concentration and degree of fatness innonreproductive mature monogastrics (10, 257, 284)and ruminants (216, 323). Insulin from the peripheryis actively transported into the CNS via a saturablemechanism consistent with insulin binding to blood-brain barrier (BBB) insulin receptors and subsequenttranscytosis through microvessel endothelial cells (25,26, 286). Within the CNS, insulin binds to specific insu-lin receptors located on neurons and glial cells (19, 145),and some of the highest concentrations of insulin recep-tor-expressing neurons are found in the areas of thebrain which are important for the control of food intakeand energy metabolism (19).

The effect of insulin on the regulation of food intakemay depend on chronic infusions and acute injectionsmay have no effect (255), although acute effects havebeen reported (144). When insulin is chronically in-jected ICV in low doses, intake and BW are reduced


Figure 6. The changes in daily food intake in dairy cows duringa long-term hyperinsulinemic-euglycemic clamp. The studies in-cluded are: 1 McGuire et al. (218), 2 Griinari et al. (130), 3 Marcleet al. (212), 4 Annen et al. (6), 5 Giesy and McGuire, preliminarydata, 6 preliminary data from authors lab. The daily intakes givenare as DM except in study four, which are given in kilograms as-fed.

in rats (42, 54, 160, 217, 253, 262, 326), baboons (338),and sheep (116). Insulin antibodies administered ICVincreased intake and weight gain (218, 308). Strubbeand Mein (308) observed that injection of insulin anti-bodies into the ventromedial nucleus stimulated noc-turnal feeding in rats, whereas injection in the lateralhypothalamus had no effect, suggesting that endoge-nous insulin at the ventromedial nucleus acts to inhibitfeeding. The responses to ICV infusions of insulin onintake and BW in rats seem dependent on the nutrientcontent of the diet (55). The largest effect on intake wasobserved when rats were given a high carbohydratediet. A minor response was observed on fat-based diets.Insulin can bind to insulin-like growth factor I (IGF-I)receptors and mimic the response of IGF-I. However,food intake is most likely not affected via IGF-I-recep-tors since Foster et al. (116) found the level of intake tobe depressed when infusing ICV insulin but not IGF-I.

Acute peripheral infusion of insulin causing hypogly-cemia decreased food intake in monogastrics (131) andruminants (5, 79). The decreased intake was most likelydue to hypoglycemia since glucose infusion preventsinsulin-induced hypophagia in man (169) and in rumi-nants (155). Chronic infusion of insulin in situations ofnormo- or hyperglycemia reduces intake in rats (326).In dairy cows hyperinsulinemic euglycemic clamp tech-niques applied for long-term infusions (4 d) generallydepress intake as shown in Figure 6 while short-term (4h) infusions under euglycemic conditions did not affectintake (17).


In summary, insulin may play a role in long-termintake and weight regulation in ruminants like in thestudies of Vandermeerschen-Doize et al. (323) andMcCann et al. (216). In the dairy cow, insulin may playa role in the dip in intake in late pregnancy, but itis unlikely that insulin plays any significant role indepressing intake in dairy cows in early lactation whenthe insulin concentration is low.

Glucagon and GLP-1

Proglucagon is expressed primarily in the α-cells ofthe pancreatic islands and in the endocrine cells of thegastrointestinal mucosa. In the human pancreas, pro-glucagon is the precursor of glucagon and a number ofproglucagon fragments, while proglucagon in the smallintestine is the precursor of glicentin, GLP-1, GLP-2and other fragments (2, 152). Here we will only addressglucagon and GLP-1 because these are the biologicallyactive peptides (152).

An early report (282) demonstrated that glucagoncould decrease food intake in humans. Later studieshave confirmed that glucagon reduces food intake inrats when administered peripherally (127) or centrally(168). But glucagon is most likely not acting directlyon the brain but rather on the liver since the depressiveeffect of glucagon could be prevented by hepatic vagot-omy (126, 214). Furthermore, glucagon is more potentwhen administered into the hepatic portal vein thaninto the inferior vena cava (125). When antibodiesagainst glucagon are given intraperitoneally to ratsprior to feeding, meal size and duration were enhanced,indicating that glucagon may act as satiety factor (199).

The sequence of GLP-1 (7-36) is completely conservedin all mammalian species studied, implying that it playsa critical physiological role (136). In 1996, Turton et al.(319) showed that GLP-1 powerfully inhibits feeding infasted rats and suggested that central GLP-1 is a newphysiological mediator of satiety via the paraventricu-lar nucleus of the hypothalamus and central nucleusof the amygdala. These centers are probably stimulatedvia peripheral GLP-1 passing through BBB leaks (240)or vagal pathways (2). Subsequent studies have con-firmed the profound inhibitory effect of GLP-1 on foodintake in rats through ICV administration of GLP-1 oran antagonist to GLP-1, exendin (159, 224, 317, 332).

Only few investigations are available in ruminantson the influence of glucagon and GLP-1 on food intake.Glucagon administered intravenously at physiologicalconcentrations does reduce intake in sheep (80). Circu-lating concentrations of GLP-1 are significantly higherin lactating compared to dry sheep (99). The increasedcirculating concentration during lactation is most likelydue to increased secretion, probably resulting from the


increased feed intake during lactation, since the half-life of GLP-1 does not change due to lactation. Clearly,more research is needed in ruminants on the effect ofglucagon and GLP-1 to unravel their importance inintake regulation.

Cholecystokinin

Cholecystokinin was first isolated from the porcinegastrointestinal tract (235). The CCK is perhaps thebest-studied putative endogenous satiety signal andhas been considered “the prototypic peripheral satietyhormone” (230). Therefore, it is not surprising that alarge number of reviews on CCK are available (12, 13,74, 206, 207, 279, 290, 300) in which the reader mayfind detailed information on the biology of CCK. Conse-quently, we will only give a very brief summary inthe following.

The CCK is primarily secreted from the duodenumand jejunum, but CCK-secreting cells have been local-ized throughout the gut and in the CNS, including sev-eral brain areas (13). Many different molecular formsof CCK, molecules of 58, 39, 33, 25, 22, 18, 8, 7, 5, and4 AA, have been isolated in the intestine, brain, andcirculation of multiple species. These different formsmay have different biological activities (207). Ingestionof food and particularly the digestion products of fat andprotein are potent stimuli of CCK secretion, althougheffects of these stimulators differ among species (43).Also, there is increasing evidence for a CCK-releasingfactor of intestinal origin (206). In ruminants, Choi andPalmquist (62) tested the effect of fat feeding on plasmaCCK concentrations in cows and observed a dose-depen-dent increase in CCK 3 h postfeeding. Furuse et al.(121), however, did not observe any differences inplasma CCK concentration around meals of concen-trates and hay in cows, which might reflect the continu-ous flow of digesta from the rumen or just the limitednumber of cows (n = 3) in this study. The numerousbiological actions of CCK (74) are now known to actthrough two different receptors, a peripheral type(CCK-A receptor) and a brain type (CCK-B receptor)(207).

The CCK may cause satiety via various peripheralmechanisms such as smooth muscle contractile effects,decreased gastric emptying, and direct vagal stimula-tion (290). The direct vagal effect on satiety suggeststhat food in the intestine causes the release of CCK,which acts on CCK-A receptors in the vagus nerve toprovide sensory information to the VMH and PVN. Thesatiety effect of CCK varies with species, age, feeding,and experimental conditions (13, 74, 114, 279, 290, 300).In sheep, ICV injection of different doses of CCK-8,believed to be within the physiological range, caused a


dose-dependent hypophagia (81, 82) and decreasedmeal size (83). The ICV injections of CCK-8 also de-creased the rate and amplitude of rumen contractions(46, 83). Larger forms of the CCK molecule (CCK-33)likewise cause satiety when administered ICV in sheep(84). The most convincing evidence for a satiety role ofCCK is the ICV injection of specific CCK-antiserumthat caused a significant hyperphagia in sheep (85).

Somatostatin

Brazeau et al. (40) isolated and characterized a hypo-thalamic peptide with a potent inhibitory effect on so-matotropin release. Somatostatin (SS), a tetradecapep-tide, is not only secreted in the brain but also in thegut (341). Via neuroendocrine, exocrine, paracrine, andendocrine mechanisms, SS plays numerous regulatoryroles in the organism, including regulation of feed in-take. Manipulation of the SS concentration in the brainindicates a central depressing effect of SS on intakein most experiments with rodents (7, 151, 208) andruminants (303, 304), although not in all (203, 209).Peripherally administered SS has likewise been shownto reduce feeding in rats and baboons (203, 209) by avagal mediated mechanism indicating a link betweenthe gastrointestinal tract and the central regulation offeed intake in the brain. However, SS is effective onlyin animals with mild degrees of hunger (203). Immuni-zation against SS in cattle also indicates that circulat-ing SS reduces VDMI. In a meta-analytic evaluation of11 studies, Ingvartsen and Sejrsen (167) found thatgrowing cattle immunized against SS consumed moreDM (4.2 ± 1.4%), had a higher daily gain (11.4 ± 2.3%),and improved feed conversion ratio (3.3 ± 2.0%) com-pared to controls.

SIGNALS FROM THE IMMUNE SYSTEMREGULATING INTAKE

Recently, Weingarten (334) argued for the impor-tance of the immune system in ingestive behavior. Theimmune system can cause hypophagia via cytokines,which are polypeptide mediators produced by a varietyof immune cells. The cytokines that most profoundlyaffect intake are those involved in the acute phase in-flammatory responses (APR), tumor necrosis factor-α(TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) (172, 192), but cytokines such as interferons, IL-8and other chemokines or intercrines may also inducehypophagia (250). A commonly used model for studyingthe effects of APR cytokines is to use lipopolysaccharide(LPS) administration as a tool to provoke APR. Indeed,LPS-administration decreases food intake and BW inhamsters (135), rats (251), mice (97, 98), and cattle (92).


Tumor Necrosis Factor-α

The hypophagic effect of cytokines has been demon-strated by peripheral or central injection of cytokinesor by blocking their action. The TNF-α reduces intakein rodents when administered intraperitoneally (29).The administration of antibodies against TNF-α en-hanced food intake in tumor-bearing rats, although theeffect was not dramatic and was only statistically sig-nificant on d 2 after injection (299). Both acute (254)and chronic (256) ICV infusion of TNF-α reduce intake,but not to the extent of IL-1β (256). In pigs, both LPS-administration and ICV infusion of TNF-α reduce in-take (333). In cattle, low doses (<0.5 mg/100 kg) of re-combinantly derived bovine TNF-α caused no effect,while prolonged treatment with higher doses (>0.5 mg/100 kg) caused hypophagia, depression, cachexia, anddiarrhea (32). The hypophagic effect of TNF-α on intakein ruminants may, in part, be due to a TNF-mediatedinhibition of rumen motility (321).

Interleukin-1-β

The IL-1 reduces intake when acutely administeredto rats peripherally (197, 221) or ICV (249, 254). Simi-larly, chronic administration of IL-1β ICV to rats for 3to 7 d reduces intake considerably (101, 150). The ICVtreatment with IL-1 receptor antagonist concomitantlywith IL-1β (252) or in relation to colitis (220) has alsoshown the role of IL-1β in hypophagia and that it ismediated by a direct action in the CNS. The hypophagiafollowing an IL-1β administration is due to a reductionin both meal numbers and their size (249). Very littleinformation is available on IL-6 and food intake, butICV administration of IL-6 and a soluble IL-6 receptorin rats indicates a role of IL-6 in intake regulation (280).

Acute phase inflammatory response cytokines proba-bly act adaptively or synergistically on intake (302)and may also interact with leptin. An increased leptinexpression is observed after an LPS administration(135, 274) probably caused by TNF-α that increasesleptin secretion (102). Leptin is also increased by exper-imentally induced infections in rats (ileitis) (15) andmice (peritonitis) (232). This suggests that leptin maybe involved in the APR and hypophagia in relation toinflammation. It is possible that leptin participates inthe host response to inflammation by modulating thehost immune and cytokine responses (96), but leptinper se is not essential in the hypophagia caused byinfections since LPS-treatment of leptin-receptor defi-cient (db/db) mice also caused hypophagia (98).

Not only are the cytokines, such as TNF-α, IL-1-β,and IL-6 affecting intake, they are also having a majorimpact on metabolism. It is beyond the scope of this


Figure 7. A simplified diagram showing putative peripheral sig-nals involved in intake regulation in dairy cattle. Humoral signals(full lines) due to pregnancy, estrus, adipose tissue mass, pancreatichormones, and cytokines from the immune system may down-regu-late intake. Progesterone has no direct effect on intake but blocksthe depressive effects of estrogen on intake. The gut peptides chole-cystokinin (CCK), somatostatin (SS) and glucagon-like peptide-1(GLP-1) is secreted from the small intestine into the circulationwhere they act on specific receptors of vagal efferents (broken lines).Stimulation of these afferents activates central neural pathwaysresulting in down-regulation of intake. Gut peptides, at least GLP-1, may also cross the blood-brain barrier and act via receptors in thebrain. The liver senses metabolic processes like β-oxidation (filleddiamond) providing satiety signals mediated by vagal afferents (bro-ken lines).

review to address this interesting field here and readersare referred to recent reviews (93, 94).

INTEGRATION OF METABOLISM ANDINTAKE REGULATION

In Figure 7, a simplified diagram showing putativeperipheral signals involved in intake regulation in dairycattle is given. In the following, we will briefly touchon neuropeptides that may be involved in the regulationof intake and their role in integrating peripheral signalsand metabolism.

Central Mechanisms and Integration

Although much remains unknown, some progress hasbeen made in understanding how the brain processesperipheral information via neuropeptides. We will notattempt to review all the neuropeptides potentially in-volved in intake regulation (see Table 3) but will focuson some intake-stimulating neuropeptides such as neu-ropeptide Y (NPY) and galanin believed to be importantin mediating the effects of peripheral signals to thebrain. We have already dealt with some intake de-


pressing gut peptides (GLP-1, CCK, SS) and the neuro-peptide CRF and will only touch on these in order toexplain aspects of integration.

The NPY is found in cell bodies and nerve terminalsof many areas of the brain, particularly those involvedin intake regulation and energy balance. Acute injec-tions of NPY ICV cause hyperphagia in satiated rats(33, 65, 222) and sheep (226, 227). Chronically adminis-tered NPY over 7 d (53) results in sustained hyperpha-gia and increased body fat accumulation in rats (343),while chronic ICV administration of NPY-antibodiescauses hypophagia (88). When administered centrally,NPY is one of the most potent inducers of food intakeand is able to increase intake and daily gain twofoldand sixfold, respectively (305). Like NPY, galanin iswidespread in the brain, but with particularly high con-centrations in the PVN. In rats, ICV injection of galanincauses hyperphagia (189), often with a preference forfat (190, 315). We have found no information on galan-in’s effect on feeding in ruminants.

There is now evidence for an activation of the ARN-PVN NPY pathway in response to signals associatedwith negative energy balance. Negative energy balancedue to feed restriction (1, 174, 270), intense exercise(205), or lactation (301) is accompanied by increasedlevels of NPY mRNA or rise in concentration of thepeptide itself in different brain regions. It is speculatedthat NPY plays an important role in the increasedVDMI in early lactation.

The response to negative energy balance is, at leastin part, mediated by reduced negative feedback fromleptin and insulin. Leptin administered centrally re-duces the NPY expression and synthesis in the hypo-thalamus of rodents (75, 269, 283, 285) and ewes (147).However, leptin does not only mediate its effect on in-take via NPY. In studies with ob/ob mice and wild-typemice in which NPY was knocked out, the ob/ob micedid not completely normalize their weight and the wild-type lacking the NPY still controlled intake and BWnormally (241). Other mediators of leptin action suchas proopiomelanocortin, melanocortin stimulating hor-mone, and aguti-related peptide are likely to be in-volved as indicated in recent reviews (106, 241). Indeed,Sahu (269) has shown that central administration ofleptin decreased food intake and weight gain in associa-tion with a decrease in hypothalamic galanin, melano-cortin-stimulating hormone, proopiomelanocortin, andNPY gene expression and an increase in neurotensinegene expression. Furthermore, CRF seems to be in-volved since leptin administered to rodents peripherally(73) or centrally (269, 285) increases CRF expressionor secretion. The intake depressive effects of insulinmay also be mediated, at least in part, via NPY since


ICV infusion of insulin can inhibit the rise in NPYmRNA levels that usually occurs during fasting (287).

Leptin and Neuropeptides as Integratorsof Intake and Metabolism

In previous sections, we have discussed the role ofboth peripheral and central signals in intake regula-tion. Clearly, all the peripheral signals discussed inprevious sections exert a variety of other biological func-tions apart from being involved in intake regulation.As an example, leptin also affects energy expenditure,glucose metabolism, insulin secretion and action, theadrenal axis and hormones of the growth hormone axisas discussed in recent reviews (37, 156, 158, 328). Mostof these metabolic processes may not necessarily bedirectly affected by leptin since the effect could be medi-ated via leptin-induced changes in NPY and CRF (37,336).

There is little doubt that animal intake is highlyintegrated with its metabolism and environment andthat this integration takes place in the brain. However,the majority of the information available is on rodentsor at least monogastrics. Differences among species cannot be ruled out and much work has yet to be done toimprove our understanding of intake regulation and itsintegration with metabolism, particularly in cattle.

CONCLUDING REMARKS AND PERSPECTIVES

In the present review we have focused on the dip inintake that occurs around calving and the mechanismsand signals that may mediate this dip. The dip in intakein periparturient cattle coincides with adaptations inmetabolism to the advancing pregnancy and forthcom-ing lactation. This dip in intake occurs not only in rumi-nants but also in monogastric animals such as the ratand seems to be a normal adaptive event in peripartur-ient animals. However, in some circumstances the mag-nitude and duration of the dip can increase consider-ably, possibly influencing the health and well-being ofthe periparturient cow.

Physical constraints play an important role in intakeregulation, but we believe that its role has been overem-phasized and have described metabolic factors that mayplay an equally important role in intake regulation inthe periparturient cow. These factors include nutrients,metabolites, reproductive hormones, stress hormones,leptin, insulin, gut peptides, cytokines, and neuropep-tides such as NPY, galanin, and CRF. The dip in intakein late pregnancy may be mediated via body reservesand endocrine factors in response to the advancingpregnancy. Leptin and insulin are likely to play anincreasing role in the concurrent increase in body fat-


ness. Also, estrogen reduces intake during the latestages of pregnancy and the first days of lactation. Themechanisms involved in intake regulation in early lac-tation are not very well understood. The general in-crease in intake in early lactation is speculated to bedue to an increase in neuropeptides, such as NPY andgalanin. Furthermore, a reduction in intake depressingsignals from hormones such as leptin and insulin maylikewise stimulate and increase intake in early lacta-tion. Nutrients and their metabolism may also influenceintake. Particularly, feedback signals from the oxida-tion of NEFA in the liver are speculated to down-regu-late intake in late pregnancy and early lactation whenmobilization is high. This mechanism may also, at leastin part, explain the lower intake in fat cows mobilizingmore body reserves than thin cows in early lactation.Little is known in ruminants on how specific nutrientsaffect the release of satiety peptides from the gut. How-ever, it seems likely that the large variation in intakereduction observed when different fat sources are in-fused into the abomasum may be due to differencesin their ability to stimulate, e.g., CCK secretion. Theimmune system may also affect intake during infection.During the APR, cytokines that may severely reduceintake are released.

The integration of signals involved in intake regula-tion takes place in the brain. The effect of several ofthe peripheral signals is mediated via central neuropep-tides. The neuropeptides are not only involved in thecentral regulation and integration of intake but alsoexert multiple effects on metabolism, which indicatestheir role in integrating metabolism and intake regu-lation.

Whether factors affecting intake in monogastricshave similar effects in the dairy cow needs to be tested.Furthermore, there is a need for long-term studies giv-ing detailed information on intake, performance, andphysiological parameters relevant for forming conceptson the desire of the dairy cow to store and mobilize bodyreserves at different physiological states. Physiologicalmeasures reflecting, e.g., body reserves and mobiliza-tion in early lactation have the potential to provideuseful physiological indicators of abnormally low intakeand subsequent metabolic stress. A better understand-ing of the mechanisms in intake regulation, includingits integration with metabolism, should result in im-proved animal selection and feed management and,thereby, better performance, health, and animal well-being.

Before trying to improve feed management, weshould try to understand the desire of the animal. Forexample, is the cytokine-mediated hypophagia associ-ated with infection beneficial to the animal? Hypopha-gia may seem somewhat paradoxical since it may lead


to metabolic diseases such as fatty liver and ketosis.However, the behavior of sick animals may be an orga-nized strategy that facilitates recovery and survivalof the animal and not a maladaptive response to thedisease. This has been exemplified in the study of Mur-ray and Murray (234) who studied the role of hypopha-gia as a mechanism of host defense mechanisms. Theydid so by comparing mortality in Listeria-infected micewith that of Listeria-infected mice force-fed to the sameenergy intake as in control mice. Ad libitum fed infectedmice ate 58% of controls. Force-feeding of infected miceincreased mortality (93 vs. 43%) and shortened survivaltime (3.9. vs. 8.7 d), suggesting that hypophagia playsa significant role in the early host defense and survival.

A better understanding of the mechanisms regulat-ing intake and metabolism, and particularly their inte-gration, is important for the development of better con-cepts in predictive models for intake, production, energybalance and health—not implying, though, that it isnecessary to make models more complicated by addingnumerous physiological parameters. To advance ourunderstanding of intake regulation, and ability to ma-nipulate intake in the periparturient cow, we need tofurther characterize the adaptive changes occurring inmetabolism around parturition and the desire of cowsto mobilize body tissue in support of lactation. Informa-tion is lacking on a number of important areas of intakeregulation in dairy cattle, as indicated in this review.We hope that some of the issues and assumptions putforward in this paper will stimulate further critical ex-periments which in turn will lead to a better under-standing of intake regulation in early lactation and itsintegration with metabolism.

ACKNOWLDGEMENTS

We wish to thank Dale Bauman, Mark McGuire,Miko Griinari, and Tim Marcle for giving us access tofeed intake data from their studies on insulin using thehyperinsulinemic-euglycemic clamp technique. Fur-thermore, we thank Karin V. Østergaard for her skilledassistance in preparing the manuscript and the staffat our library for providing us with the large numberof articles used for this review. The Danish Ministry ofFood, Agriculture and Fisheries is acknowledged forthe funding of a previous project (GRU-SH-2) importantfor this work and support to the projects HUS97-2 andHUS97-3.

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