Food Regulation Rob Contreras, Ph.D. 018 Longmire [email protected] 644-1751.
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Transcript of Food Regulation Rob Contreras, Ph.D. 018 Longmire [email protected] 644-1751.
Two Principle views of food intake control
• Food intake triggered by:– Depleted energy stores
• Less adipose tissue
• Less glucose or lipid
– Primed to eat unless inhibited• Signals from meals
• Onset not from acute need
• Caloric homeostasis
Caloric homeostasis
• Preserve cellular metabolism• Three macronutrients
– Carbohydrates, lipids, proteins
• Most tissues of the body– COH to glucose, or lipids to free fatty acids
• Liver– Lipids
• Brain– Glucose (backup - ketone bodies)
Two Distinct Metabolic States
• Prandial (fed) state– Abundance of newly ingested & absorbed
nutrients in blood
• Postabsorptive (fasted) state– Absence of entering calories from GI tract into
circulation– Reliance on metabolic fuels less recently
ingested and stored
Caloric homeostasis
During prandial state, energy is stored – as glycogen (liver and muscle) or triglycerides (adipose tissue) – facilitated by insulin – ANABOLISM
During postabsorptive state, energy is utilized for metabolism – facilitated by lack of insulin – either glycogenolysis (to produce glucose) or lipolysis (free fatty acids and glycerol) – CATABOLISM
Regulation of feeding is a balancing act – between energy storage (anabolism) and use (catabolism)
Liver: Key organ in energy traffic
• Prandial/fed– COH to glycogen– Lipogenesis (also in adipose tissue)
• Postabsorptive/fasting– Glygogenolysis– Ketogenesis– Glugoconeogenesis
• Control system = hormones + ANS
Insulin
• B cells of the pancreatic islets
• Direct proportion to blood glucose
• Also amino acids & ketone bodies
• ANS innervates pancreatic islets– PNS (ACh) stimulates secretion– SNS (NE, alpha-adrenergic) inhibits secretion
Caloric homeostasis: Insulin
Insulin is low during fasting
It is increased in cephalic phase by sight, smell and taste of food
When food enters stomach, there are direct actions of digestive hormones on insulin secretion – during gastrointestinal phase
Substrate phase results from stimulation of pancreas by metabolic fuels (mainly glucose)
Insulin serves to promote energy utilization and storage
Insulin & body fat
• More body fat, the more insulin secretion• Number of insulin receptors on adipose
tissue & skeletal tissue inversely related to adiposity
• Reciprocal relationship between insulin secretion & tissue sensitivity to insulin
• Insulin ensures efficient use & storage independent of body weight
Diabetes mellitus
• Type 1 or Insulin-dependent– High plasma glucose– Cannot be utilized & excess excreted -sweet
urine– Caused by deficiency in B cells & insulin
secretion
• Type 2 or noninsulin-dependent– 85-90% have insulin, but are obese & resistant
to insulin in promoting fuel use & storage
Two Principle views of food intake control
• Food intake triggered by:– Depleted energy stores
• Less adipose tissue
• Less glucose or lipid
– Primed to eat unless inhibited• Signals from meals
• Onset not from acute need
• Caloric homeostasis
Caloric homeostasis and food intake: SatietyMeal size does not depend on time since the last meal
– however, the size of a meal determines how long before the next one
Eating appears to be inhibited by a “satiety signal” that decreases over time
Caloric homeostasis and food intake: Satiety factors
Gastric distension serves as one satiety signal:
Rats with gastric fistulas, which do not allow fluid into the stomach, do not terminate meals as readily
Cholecystokinin (CCK) is secreted by the stomach during meals and also serves as a satiety factor
Several other molecules, including insulin, bombesin-like peptides, and glucagon may also be satiety factors – these factors control meal size
Satiety Signals• Gastric distention
– Stomach endowed with stretch receptors– Vagus to NST & area postrema
• Cholecystokinin– Secreted during meals– Receptors on Vagal afferent fibers that also convey
gastric stretch signals– CCK + stretch act synergistically to inhibit food intake
• Post-gastric– Nutritional signals from intestines to liver
• Body Weight– Forced weight loss or weight gain
Body weight and food intake: Leptin
4) Ingestion of food generates
satiety signals; L- and I-sensitive pathways
interact with satiety circuits to regulate meal
size
3) Low leptin and insulin in brain stimulate
eating and suppress energy
expenditure
2) Leptin and insulin suppress brain anabolic circuits and activate catabolic circuits
1) Leptin and insulin circulate in proportion to body fat and energy balance
Body weight and food intake: Leptin
Mutants of the Ob-Rb receptor (for leptin) are both hyperphagic and obese – i.e., they do not detect circulating leptin and overeat
Leptin is secreted by adipocytes and circulates in proportion to the amount of body fat
Overton lab goal is to determine mechanisms linking regulation of energy balance and
cardiovascular function
OverfeedingCold exposure
Caloric deprivationThermal neutrality
VO2 , sympathetic activity, heart rate, blood pressure
+
-VO2
VO2, sympathetic activity, heart rate, blood pressure
Central control of food intake
Neurons responsible for the central regulation of food intake are in several areas of the hypothalamus
These areas include the
lateral hypothalamic area (LHA),
the ventromedial hypothalamus
(VMH), the arcuate nucleus
(ARC), and the
paraventricular
hypothalamus (PVH)
Central control of food intake: VMH lesions
Lesions of the VMH produce hyperphagic, obese rats – this is not due to destruction of a “satiety center,” but to an increase in autonomic tone, which leads to increased fat deposition – i.e., a new body weight “set point” – as a result of increased insulin
These animals become hyperphagic in an attempt to maintain this new body weight
Lesion-Induced Weight LossLesions of the LH caused aphagia.
Dual Center hypothesis: VMH - satiety center; LH - hunger center.
Not due to hunger center, but to akinesia and sensory neglect; resemble Parkinson’s disease
Neuropeptides & control of food intake
• Two major classes– Anabolic
• Increased eating
• Decreased energy expenditure
• Increased body fat
– Catabolic• Reduced food intake
• Increased energy expenditure
• Loss of body fat
Central control of food intake: Signaling pathways
Arcuate neurons
NPY: neuropeptide Y – increased food intake
AgRP: agouti-related protein – increased food intake
POMC: proopiomelanocortin – precursor of -MSH
-MSH: -melanocyte-stimulating hormone – decreased food intake
CART: cocaine-amphetamine-related transcript – decreased food intake
PVN or LHA neurons
MCH: melanin-concentrating hormone – increased food intake
Orexin (hypocretin): also involved in sleep – increased food intake
CRH: corticotropin-releasing hormone – decreased food intake
Oxytocin: also involved in uterine contraction and milk letdown – decreased food intake
Catabolic pathway
• Alpha-MSH & CART– Activated by leptin & insulin– ICV-3rd = decrease food intake, increase
energy expenditure, weight loss– Bind to melanocortin receptors (MC3 & MC4)
in PVN, VMH, LH– No MC3, obese without overeating– No MC4, obese with overeating
Anabolic pathway• NPY & AgRP
– Inhibited by leptin & insulin– ICV-3rd = increase food intake, decrease energy
expenditure, weight gain– NPY neurons to PVN (NPY receptors); NPY in PVN
increase food intake– AgRP = antagonist of MC3 & MC4 receptors– AgRP to 3V, increase food intake by blocking action of
alpha-MSH on MC receptors– NPY directly stimulate anabolic pathway; AgRP
antagonizes tonically active catabolic peptides
Other peptides
• Orexin A & MCH– Injected in brain - increase in food intake– Neurons in LH, LH lesion aphagia partially due to
reduced orexin and MCH
• Oxytocin– CCK, gastric distension, hyperosmolality– ICV oxytocin decreases food intake
• CRH (stress pathway)– Icv CRH decreases food intake mediated through
oxytocin axons projecting to CNS, not pituitary
Leptin and insulin inhibit NPY/AgRP neurons and stimulate POMC/CART neurons – increased leptin and insulin lead to decreased food intake
Central control of food intake: Arcuate nucleus
Leptin and insulin deficiency activates NPY/AgRP neurons in the arcuate n.
Release of NPY and AgRP into PVN and LHA leads to increased food intake and obesity
Leptin and insulin deficiency also inhibits arcuate neurons containing POMC, leading to decrease in -MSH release and obesity
AgRP inhibits melanocortin receptors
Central control of food intake: Obesity
Arcuate neurons innervate second-order neurons in the PVN, PFA and LHA.
CRH, TRH and oxytocin neurons in the PVN produce anorexia
Orexin and MCH neurons in the PFA and LHA increase feeding
Central control of food intake: Second-order neurons
Increased Leptin and insulin levels activate POMC neurons in the arcuate n.
Release of POMC results in elevated -MSH levels and decreased food intake (anorexia)
At the same time leptin and insulin inhibit arcuate neurons containing NPY/AgRP, also leading to decreased food intake
Central control of food intake: Anorexia
Leptin and insulin inhibit NPY/AgRP neurons and excite -MSH/CART neurons in arcuate n.
NPY/AgRP neurons inhibit PVN and excite LHA, whereas -MSH/CART neurons stimulate PVN and inhibit LHA
PVN has catabolic action, LHA has anabolic action – through connections in the brainstem (e.g., NST and area postrema)
Central control of food intake: Signaling pathways
Leptin and insulin
Central control of food intake: Signaling pathways
Balance between satiety and adiposity signals
The End