Post on 17-May-2015
Fat – good or bad?
Dr. Katarina KosSenior Clinical Lecturer
Obesity Lead, RD&EExeter
June 2012
• What is the definition of obesity and fatness?
• Fat tissue health• Regulation of appetite and adipose tissue
mass: the brain-gut-fat axis
Overview
1 2 3 4 5
1 2 3 4 5
• Body Mass Index: Body weight (kg)/ height squared (m2)
Definition of obesity
Category (adults) BMI range (kg/m2)
UNDERWEIGHT <18.5
NORMAL 18.5-24.9
OVERWEIGHT 25-29.9
OBESE >30
MORBIDLY OBESE >40
Obesity is an accumulation of fat mass, which is clinically difficult to measure and standardise
• Waist circumference (cm)
• Waist-to-hip ratio• Skinfold thickness (biceps, triceps, subscapular)• Fat mass (DXA scan, MRI scan or Bodpod)
Determination of ‘fatness’
Men Women
Low <94 <80
High 94-102 80-88
Very high >102 >88
upper body distribution : android, male, central, upper-body segment, or "apple"
lower body fat distribution: gynoid, female, lower-body segment , or "pear“ shape
What factors determine fat distribution? ◦ Ethnic background◦ Gender◦ Age
Adipose tissue distribution
Function of adipose tissue
White versus brown fat
•Storage of triglycerides- surplus energy
•Insulation
•Endocrine:• appetite • immunregulation
•Autocrine/paracrine: • immunregulation• FFA regulation: lipogenesis and lipolysis
Increased FFAdeposition with Insulin
Action of insulin on adipose tissueAction of insulin on adipose tissue
WAT cell and its productsTriglyceride droplet
Cell nucleus
Macrophage
Endothelial cell
Fatty acidsGlycerol
ChemokinesIL1,IL6, IL10, IL18PAI-1TNFalphaResistinMCP-1
CollagenSPARCVEGFNGF
AdiponectinLeptinVisfatinVaspinChemerinRBP411betaHSDAnigotensinogenEstrogen
Fibroblast
Synapses /Innervation
Kos K, Curr Opinion Invest Drugs, 2009
Adipokine-related dysfunctionsSkeletal system
Bone Fat deposition
Joints Osteoarthritis, Rheumatoid arthritis, SLE
Muscle Insulin resistance, Ectopic fat deposition
Brain Cerebrovascular disease, Alzheimer's disease, ? Multiple sclerosis
Blood vessels Endothelial dysfunction, Atherosclerosis, Hypertension
Heart Cardiovascular disease, Fibrosis
Immunsystem Systemic inflammation, Sepsis
Liver Hepatosteatosis, Hepatitis, Cirrhosis
Pancreas beta-cell apoptosis, diabetes
GI-tract Inflammatory bowel disease
Kindney Chronic kidney disease, diabetic nephropathy
Lungs Lung injury, COPD
Others: Sleep apnoea syndromeDyslipidaemiaPolycystic ovary syndromeInfertilityCancer
Adipose tissueKos K, Curr Opinon Invest Drugs 2009
After a 2 year loan to the United States Michelangelo’s David returned to Italy
His proud sponsors were:
Lean subcutaneous WATObese subcutaneous WAT
Able to expandInflammation
Smaller cells
Hypoxia
Fibrosis
Fibrosis
Hypoxia Inflammation
Disturbed microcirculation
?
Ectopic fat deposition
• Liver
• Muscle
• Perivascular
• Epicardial
• Pancreas
• ‘Omental/visceral’
Lee, et al AMJP 2009
Congenital LD
Familial partial LD
Acquired LD HIV-relatedHAART-induced
Age at onset birth puberty <20 years any
BMI normal or ↓ normal to ↑ normal to ↑ normal
Genes CGL1(AGPTAT2),CGLT2 (BSCL2)CAV1
FPLD2(LMNA), FPlD3 (PPARG)Akt 2ZIMPSE24
--- ---
Gluteal fat ↓↓↓ ↓↓ ↓ to ↑ 0-↓
Limb fat ↓↓↓ ↓↓↓ ↓↓ 0-↓↓
Trunk fat ↓↓↓ ↑↑↑ 0-↓↓ ↑↑-↓↓
Hepatosteatosis
present possible In generalized LD
possible
Diabetes Very common Depending on mutation
In generalized LD Common
Acanthosis nigricans
present present possible rare
Other Features
Hirsutism, bone cysts. CGLT2: mental retardation, cardiomyopathy
--- Autoimmune disorders, low C3, membranoproliferative glomerolunephritis
--
Modified from Hegele et al, J Lipid Research, 2007
Congenital LD
Familial partial LD
Aquired LD HIV-related LD
Fasting insulin
↑↑↑ ↑↑ 0-↑↑ ↑-↑↑↑
Triglyceride ↑↑↑ ↑↑↑ 0-↑↑ ↑-↑↑↑
Free fatty acids
unknown 0-↑ unknown ↑↑-↑↑↑
Leptin ↓↓↓ ↓↓ ↓ 0-↑
Adiponectin ↓↓↓ ↓↓ ↓↓ ↓↓
CRP unknown ↑↑ unknown 0-↑
TNFalpha unknown ↑↑ unknown ↑↑↑
Adapted from Hegele et al, J LipidResearch, 2007
Wong S, et al. Diabetologia 2005
Collagen and insulin resistance
Khan et al, Mol Cell Biol, 2009
Adiposopathy Fat disorders:
◦ Fat inflammation◦ Fat hypoxia◦ Fat fibrosis◦ Fat ischemia◦ Fat tissue failure
◦ ? Insulin resistance
'Good' baby fat keeps adults slim
Adults who retain their 'good' baby fat may be buffered against obesity and type 2
diabetes, scientists believe.
Unlike the regular white fat, which stores energy, good brown fat, actively burns calories for heat,
but has been thought only to exist in childhood.
Researchers at the J oslin Diabetes Center not only found adults still had brown fat, but that slim
adults had more of it than fatter ones.
Women appear to have more 'good' brown fat
Brite fat cells
Adipose-brain/gut crosstalk
Liking food is different from wanting food
What makes you eat?
fMRI image
Neuronal insulin pathways E.g. NIRKO mice, have
increased feeding behaviour
Reduced insulin evoked response of insulin resistant subjects
Bruning JC, et al. Science 289:2122–2125, 2000Anthony et al, Diabetes 56: 2986-2992, 2006
Leptin as treatment of obesity?
Adipose endocrinology
Feedback mechanisms
LeptinAdiponectin?
Hypothalamus
Tractus solitarius
Kos K, et al JCEM 2007
Sympathetic innervation
Leptin and blood brain barrier
Banks W, AJP, 2002
Gut hormones: Ghrelin
Effects of three types of macronutrient ingestion on plasma acyl-ghrelin (A) and
total ghrelin (B) levels expressed as a percentage of their respective baseline
values.
GLP-1What do you know about GLP-
1 metabolism?
GLP-1 receptor in adipose tissue GLP-1 enhances adipogenesispeople with higher expression have
done better after bariatric surgery ( Vendrell J, Endocrinology 2011)
DPP-IV and fat tissue
Why are DPP-IV inhibitors weight neutral?
Kos K, Diabetes, Obesity and Metabolism, 2009
DPP-IV expression in abdominal Sc tissue
DP
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A e
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0
50
100
150
200
250
Sc Lean
Sc Obese
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SummaryFat tissue is not to be mistaken
by surplus lipidsAdipose tissue is to compensate
for lipotoxicityDietary surplus of FA is
detrimental to metabolic health
Adipose tissue a victim of overeating
‘Not glamorous but essential’
"You better cut the pizza in four pieces because I'm not hungry enough to eat six.“
Yogi Berra
When picking up his take away pizza: