ESR [017] Endocrine Aspects of Obesity 2024-2025 PDF

ESR : Endocrine Aspects of Obesity Medical Biochemistry 2024/2025  NEWGIZA UNIVERSITY Aim To understand the roles of adipose secretion of cytokines and hormones, in the development of insul...

ESR : Endocrine Aspects of Obesity Medical Biochemistry 2024/2025  NEWGIZA UNIVERSITY Aim To understand the roles of adipose secretion of cytokines and hormones, in the development of insulin resistance, metabolic syndrome, inflammation, hypertension, cardiovascular disease and cancer.  NEWGIZA UNIVERSITY Objectives After this lecture you should be able to: Explain the risks associated with obesity. Describe examples of how mouse models of obesity have improved our understanding of the control of appetite and energy expenditure. Appreciate the importance of adipose tissue, as illustrated by lipodystrophies. Understand the potential importance of subcutaneous and visceral adipose tissue in metabolic syndrome. Understand how adipocyte behavior changes during adipogenesis and in hypertrophy. Explain the contributions made by adipokines (leptin, adiponectin and inflammatory cytokines) to insulin resistance, hypertension, cardiovascular disease, and cancer. Obesity NEWGIZA UNIVERSITY Obesity is the most common nutrition-related disorder in the western world, and in developing nations as well. It reduces life expectancy due to increased risk of associated disease. Adipose tissue Was previously seen as an energy source with large amounts of triacylglycerol. Adipose tissue is now recognized as an important endocrine tissue. Its secretory profile is disturbed in obesity.  NEWGIZA UNIVERSITY Risks of Obesity Obesity with BMI > 30 kg/m2 is associated with increased risk for: Type II diabetes Hyperinsulinemia Glucose intolerance Hypertension and stroke Coronary heart disease Some cancers (breast, endometrial, ovarian, gall bladder, colon) Metabolic Syndrome: NEWGIZA UNIVERSITY Metabolic syndrome is a group of five risk factors that increase the likelihood of developing: Type 2 diabetes heart disease stroke The five risk factors are: increased blood pressure (> 130/85 mmHg) high blood sugar levels (insulin resistance) excess fat around the waist high triglyceride levels low levels of good cholesterol (HDL) Genetic Mouse models of obesity NEWGIZA UNIVERSITY Much of the current knowledge about obesity has arisen from preclinical research performed mostly on laboratory mouse and rat strains. These experimental models mimic certain aspects of the human condition and its root causes, ex: -complex gene-environment interactions -over-consumption of calories and unbalanced diets Genetic Mouse models of obesity NEWGIZA UNIVERSITY The Lethal yellow mutant mouse (Ay): Unable to inhibit feeding The Obese mouse (ob/ob): Does not express leptin The Diabetic mouse (db/db): Does not express the leptin receptor. The Fat mouse (fat/fat): Obesity develops relatively slowly – it is not prone to diabetes Has hyper(pro)insulinemia, but not hyperglycemia. The Lethal yellow mutant mouse (Ay) NEWGIZA UNIVERSITY This mouse carries a lethal gene (mutant agouti gene Ay) that cause the death of the organism (homozygous) that carries them. It causes ectopic expression of the agouti protein. This agouti protein is normally expressed by follicular melanocytes and alters pigment production Ectopic expression of agouti in the hypothalamus chronically antagonizes certain neurons (which inhibit feeding), so the mutant mouse is unable to inhibit feeding This mouse has: - yellow coat color - obesity - hyperleptinemia - insulin-resistance - type II DM - tumor susceptibility  NEWGIZA UNIVERSITY The Obese Mouse (ob/ob) It gains weight rapidly to become 3X the size of control mice This mouse does not express the product of the ob gene (Leptin) Action of Leptin: -it acts in the hypothalamus to depress appetite -it affects insulin signaling (Leptin’s absence causes insulin resistance) It is an animal model of T2DM: ob/ob mice develop high blood sugar, despite an increased insulin level. Administration of Leptin shows a dramatic reduction in weight in: -Obese (ob/ob) mice -Obese individuals whose obesity is due to chromosomal mutation causing Leptin deficiency  NEWGIZA UNIVERSITY The Diabetic Obese Mouse (db/db): This mutant mouse is large/obese It has increased fat deposition and hyperglycemia This mouse does not express the product of the db gene (Leptin receptor) The phenotype of this mouse is identical to the Obese mouse. Administration of Leptin to these mice cannot treat their obesity. Diet induced obesity NEWGIZA UNIVERSITY Some animal studies use specific diets to induce obesity. High fat diet: Balanced diet: 58% of Kcal from fat (lard) 11.4% of Kcal from fat (lard) Mice fed on the high fat diet exhibit impaired glucose tolerance (early type 2 diabetes): increased weight gain modest hyperglycemia insulin resistance  Diet induced obesity NEWGIZA UNIVERSITY Cafeteria diet: (this diet encourages hedonic feeding) An experimental system for studying obesity that allows rats free, “cafeteria-style” access to cookies, candy, cake (‘junk’-food): high-salt, high-fat, low-fiber, energy dense, highly palatable foods. CAF-fed mice show: Most weight gain Worst hyperglycemia highest levels of plasma FFA Higher levels of infiltrating macrophages Dramatically altered pancreatic islets CAF diet is a better model of Metabolic Syndrome than HFD. Traditional view of adipose tissue: NEWGIZA UNIVERSITY a way of storing energy for later use During Fed State During Fasting (or Exercise) Insulin stimulates the uptake of Low Insulin/Adrenaline ratio glucose for the synthesis of TAG stimulates lipolysis of stored TAGs TAGs are stored in large droplets The released NEFA enter the for later use plasma as fuel for other tissues  NEWGIZA UNIVERSITY Insulin signaling in adipocytes 1. The Phosphatidylinositol-3 Kinase (PI-3-K) Pathway: mediates the more immediate responses to insulin: Glut-4 translocation Glycogenesis Inhibition of lipolysis (shows less activity in Insulin Resistance) NB: insulin receptor substrate 1 (IRS-1) is a signaling adapter protein 2. Mitogen Activated Protein Kinase (MAPK) Pathway: It mediates the proliferative, mitogenic effects of insulin (i.e. cell proliferation) (unaffected by Insulin Resistance)  NEWGIZA UNIVERSITY Brown Adipose Tissue Primary function is thermoregulation: BAT produces heat by non-shivering thermogenesis. Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (WAT) or white fat. Brown adipose tissue is found in almost all mammals. BAT is especially abundant in newborns an in hibernating mammals Present and metabolically active in adults (after cold acclimation) Its prevalence decreases as humans age  Brown Adipose Tissue NEWGIZA UNIVERSITY adipocytes contain: numerous smaller multilocular White Adipose Tissue TAG droplets adipocytes contain: much higher number of iron- single lipid droplet containing mitochondria ➔ gives BAT brown appearance Less mitochondria more capillaries to supply the Less capillaries tissue with oxygen and nutrients and distribute the produced heat throughout the body  NEWGIZA UNIVERSITY BAT is highly innervated by SNS Upon stimulation by noradrenaline ➔ lipolysis and FA oxidation are activated The proton gradient generated by the electron transport chain is ‘wasted’ via UCP1 (thermogenin)  NEWGIZA UNIVERSITY Adipose Tissue development PPARγ (peroxisome proliferator-activated receptor-γ) is a transcription factor necessary for adipocyte differentiation and adipogenesis PPARγ PPARγ Mature Stem cell Pre-adipocyte Adipocyte Pluripotent: Appears similar to Expresses enzymes for capable of stem cell , but lipid transport and differentiating committed to synthesis into a variety of adipocyte lineage cell types Expresses insulin Doesn’t produce receptors and are enzymes needed insulin sensitive for lipogenesis, or adipokines (except Expresses adipokines: leptin) leptin, adiponectin, chemerin  Adipose tissue development: PPARγ (peroxisome proliferator- NEWGIZA UNIVERSITY activated receptor γ ) PPARγ is a transcription factor necessary for adipocyte differentiation and adipogenesis. Adipocytes secrete adipokines Synthetic ligands to PPARγ (Thiazolidinediones, oral hypoglycemics) lead to: -Improvement of insulin sensitivity -lowering of plasma glucose -altering the secretory profile of adipose tissue away from the pro-inflammatory direction (thus they are used for trt of T2DM)  NEWGIZA UNIVERSITY Lipodystrophies Disorders involving loss of adipose tissue from particular anatomical regions It may be genetic or acquired Patients often have aspects of metabolic syndrome: -insulin resistance -dyslipidemia -hypertension Symptoms can be alleviated by the administration of adipocytokines: (leptin or adiponectin)  Familial Partial Lipodystrophy 3 NEWGIZA UNIVERSITY Progressive loss of adipose tissue from extremities (begins at puberty) Etiology: mutation of PPARγ gene which codes for PPARγ Clinical picture: Hypertriglyceridemia Low HDL Increased deposition of TAGs in liver Severe Insulin Resistance ➔ Diabetes  NEWGIZA UNIVERSITY Distribution of adipose tissue There are 2 important depot (storage) sites for adipose tissue: 1-Subcutaneous adipose tissue: The largest adipose tissue depot (protective) 2-Visceral adipose tissue: the most harmful Adipose tissue includes: -apidocytes -immune cells -vascular tissue Adipokines: They are secreted by the various depots  NEWGIZA UNIVERSITY Visceral Adipose Tissue (VAT) Excess VAT may be a marker that the ability of SC fat to act as an “energy sink” has been exceeded. VAT is “hyperlipolytic”: i.e. sensitive to adrenaline ➔ releases more FAs and it is resistant to insulin signaling. The products of VAT drain directly into the portal vein to the liver. This affects liver metabolism ➔ increase production of VLDL & glucose by liver  NEWGIZA UNIVERSITY Abdominal Adiposity Factors (e.g. smoking) increase the risk associated with VAT. Waist Circumference (or waist-to-hip ratio) is only an indicator of VAT, and cannot distinguish abdominal SC fat and VAT. CT scans can more accurately distinguish abdominal SC fat and VAT. Treatment: Exercise affects VAT and improves metabolic health. Liposuction of SC fat confers no metabolic benefits. Removal of VAT can improve glucose and insulin levels. Glitazones (Thiazolidinediones) improves insulin sensitivity.  NEWGIZA UNIVERSITY Adipocyte size: Adipocytes can increase in: Number (hyperplasia) Size (20X) (hypertrophy) Hyperplasia (increase in cell number) is a relatively healthy way to increase TAG storing capacity, showing: -Adipokines here are anti-inflammatory -Adipokines are insulin-sensitizing Hypertrophy (increase in cell size) is associated with several problems, showing: -Adipokines here are pro-inflammatory -Adipokines are insulin-desensitizing -More cell death -More recruitment of macrophages ➔ inflammation  NEWGIZA UNIVERSITY Adipokines Adipose tissue secretes >50 adipokines, most of which are proinflammatory. As obesity progresses there is change in adipokine secretion. Adipokine levels are linked to: -hypertension -cardiovascular disease -insulin resistance Adipokines NEWGIZA UNIVERSITY Leptin decreases appetite increases energy expenditure has a proinflammatory effect High Leptin levels are present in obesity Adiponectin has an anti-inflammatory effect Low adiponectin levels are present in obesity Angiotensinogen is secreted by mature adipocytes. It inhibits insulin signal transduction and causes hypertrophy of adipocytes. TNF-α and IL-6: secreted by infiltrating macrophages. They cause insulin resistance.  NEWGIZA UNIVERSITY Leptin Secreted by mature adipocytes and reflects body fat. Leptin receptors are concentrated in the feeding centers of the hypothalamus. Leptin secretion increases with body fat. It fluctuates in response to feeding (in response to insulin): Increasing with overfeeding Decreasing with fasting Function: decreases appetite increases energy expenditure has a proinflammatory effect  NEWGIZA UNIVERSITY Leptin Resistance Obese individuals may have high leptin levels (Leptin resistance). Why then does Leptin not regulate their body fat? There may be a fault in: 1. Crossing blood brain barrier: Leptin crosses the blood brain barrier, the levels of Leptin found in the cerebrospinal fluid of obese individuals is relatively low compared to the high plasma levels. Central administration of Leptin can have some effect on weight loss. 2. Downstream signaling N.B.: Fructose (which does not stimulate insulin production) thus does not increase Leptin secretion. This may be one reason why such diets are associated with obesity.  NEWGIZA UNIVERSITY Other effects of Leptin 1. Role in immunity and development of immune system: administration of Leptin enhances immune response. 2. Chemoattractant: (leptin attracts macrophages) high levels of Leptin in case of obesity may be responsible for the infiltration of macrophages into adipose tissue ➔ inflammation Adiponectin NEWGIZA UNIVERSITY It is anti-inflammatory: it inhibits TNF-α secretion by macrophages. Adiponectin provides insulin sensitivity to adipose tissue. High levels of adiponectin are associated with : -decreased risk for cardiovascular problems Low levels are associated with: -obesity -hyperinsulinemia -insulin resistance -future risk of type 2 diabetes Adiponectin levels are increased by: -weight loss -exercise -synthetic ligands to PPARγ (thiazolidinediones)  NEWGIZA UNIVERSITY Inflammation in Obesity Obesity is associated with mild but chronic inflammation. High levels of markers of inflammation are present in case of obesity, e.g.: -C Reactive Protein -IL-6, IL-8, IL-1β -TNF-α The immune response is stimulated by: -recruiting immune cells -maturation of immune cells Weight loss leads to decreased level of these markers.  Inflammation in Obesity NEWGIZA UNIVERSITY Mechanism: Hypoxia in the expanding adipose tissue ➔ death of adipocytes ➔ macrophage infiltration around dead necrotic adipocytes ➔ Infiltrating macrophages may then secrete large amounts of pro-inflammatory cytokines Adipocyte death increases with the size of adipocytes. The macrophages are typically clustered around individual dead, necrotic adipocytes forming “crown-like” structures (CLS).  NEWGIZA UNIVERSITY Anti-inflammatory cytokines: -Adiponectin ( -IL-10 Both decreased in obesity Pro-inflammatory cytokines: -Leptin -Angiotensin -IL-6 All are increased in obese individuals. Renin-angiotensin system is overactive in adipose tissue of obese (responsible for inflammatory process)  Insulin Resistance NEWGIZA UNIVERSITY An inadequate response to normal levels of insulin (i.e. higher levels of insulin secretion are required to maintain normoglycemia) ➔ Long term this can lead to pancreatic beta-cell failure and type2 DM. Type2 DM Beta-cell failure Insulin resistance: Due to inhibition of the insulin signaling pathway, either by: -inflammatory cytokines, or -phosphorylation ➔ inhibiting components of the insulin signaling pathway  NEWGIZA UNIVERSITY Insulin Resistance Insulin resistance is correlated with lipid deposition in skeletal muscle and liver (ectopic lipid deposition). TAG storage spills over into VAT, skeletal muscle and liver. Leptin improves insulin sensitivity, but not in the leptin resistance seen in obesity.  Adiponectin NEWGIZA UNIVERSITY and Insulin Resistance Plasma Adiponectin levels decrease as obesity progresses ➔ Insulin Resistance ➔ Type 2 DM. Decreased obesity ➔ increased adiponectin level ➔ improved insulin sensitivity  Hypertension NEWGIZA UNIVERSITY High blood pressure is a risk factor for cardiovascular disease. Hypertension is correlated with obesity: -Increased BMI -Abdominal obesity Weight loss can decrease hypertension. Hypertension NEWGIZA UNIVERSITY An altered adipokine secretion (leptin/adiponectin) is present in case of obesity. Adipocytes secrete inflammatory cytokines which alter the behavior of: endothelial cells lining blood vessels ➔ arterial stiffness smooth muscle cells around blood vessels the renin-angiotensin system (RAS) The inflammatory cytokines may act on: -Vasodilators: e.g. nitric oxide (NO) -Vasoconstrictors: reactive oxygen species (ROS), RAS components Inflammatory cytokines are involved in hypertension by: Decreasing NO production by endothelial cells ➔ vasoconstricion Increasing ROS which further depletes NO ➔ vasoconstricion Induction of endothelial cell (EC) proliferation ➔ vasoconstricion Enhancement of vascular SMC proliferation ➔ vasoconstricion Stimulation of angiotensinogen production Hypertension & CVD: NEWGIZA UNIVERSITY Leptin/Adiponectin Leptin can lead to hypertension: (effects are enhanced in case of obesity) Production of pro-inflammatory cytokines (TNF-α , IL-6) ➔stimulation of the SNS ➔ increasing blood pressure (this is not affected by leptin resistance) Smooth muscle cell (SMC) proliferation by proinflammatory cytokines On the other hand Adiponectin leads to regulation of blood pressure: Increase NO production decrease smooth muscle cell (SMC) proliferation reduce oxidative stress Low adiponectin levels correlate with hypertension (as in case of obesity)  Hypertension NEWGIZA UNIVERSITY & the RAS system The renin–angiotensin system (RAS) is a hormone system that regulates blood pressure and fluid balance. Adipose tissue expresses most of the components of RAS system. RENIN ACE Angiotensinogen ➔ ➔ Angiotensin I ➔ ➔ Angiotensin II➔ ➔ Receptor ➔ ➔ action: Angiotensin II stimulates the adrenal cortex to produce aldosterone, which regulates blood pressure by affecting salt water homeostasis Mature adipocytes produce angiotensinogen. More angiotensinogen is produced in obesity by visceral adipocytes ➔ hypertension (seen in metabolic syndrome)  NEWGIZA UNIVERSITY Obesity and Cancer Obesity is linked with alteration of adipokine secretion and an increased risk of incidence of some types of cancer. Obesity also increases risk of: increased aggression of tumors higher number of metastases increased resistance to chemotherapy increased recurrence increased mortality Adipokines and Cancer NEWGIZA UNIVERSITY Altered adipokine secretion may lead to: Neovascularization: Some adipokines act as growth factors for cancer cells and they may promote angiogenesis (neovascularization) Metastasis: Adipose tissue appears to produce substances that favor metastasis, (e.g. Hepatocyte Growth Factor) N.B.: exercise during and after treatment can significantly improve survival  NEWGIZA UNIVERSITY Angiogenesis and Metastasis Neovascularization occurs early in tumor development. The blood vessels formed are abnormaly hyperpermeable to small molecules, plasma fluid and proteins ➔ easier for metastatic tumor cells to invade such vessels ➔ enter the circulation. These tumor cells may then reach distant sites, and potentially form new tumors (metastasis)  Plasma (Leptin / Adiponectin) NEWGIZA UNIVERSITY and Cancer Leptin: (increased levels in cancer patients) a mitogen on many cell types an inhibitor of apoptosis a promoter of angiogenesis (by expressing VEGF, HGF, TNF-α, IL-6) Tumors with increased leptin receptor are linked to poor prognosis Adiponectin: (lower levels in cancer patients) causes arrest of cell growth favors apoptosis anti-angiogenic Adiponectin correlates inversely with cancer risk and progression (hypoadiponectinemia is a marker for an aggressive phenotype) Inflammation is also linked to cancer risk, promoting aggression and metastasis.  NEWGIZA UNIVERSITY Summary Adipocytes are excellent as a storage site for TAG, but have an endocrine role that allows them to alter whole body metabolism in obesity. The secretory profile of adipocytes is altered by nutritional status, location of the depot, size of the cell, and interaction with other signaling molecules. In obesity, a response of hypertrophy (rather than hyperplasia) seems to stimulate the secretion of pro-inflammatory cytokines, and favors insulin resistance. The alteration in adipokine secretion during obesity may be responsible for many of the problems associated with obesity, in particular, the metabolic syndrome.  NEWGIZA UNIVERSITY Objectives After this lecture you should be able to: Explain the risks associated with obesity. Describe examples of how mouse models of obesity have improved our understanding of the control of appetite and energy expenditure. Appreciate the importance of adipose tissue, as illustrated by lipodystrophies. Understand the potential importance of subcutaneous and visceral adipose tissue in metabolic syndrome. Understand in outline how adipocyte behavior changes during adipogenesis and in hypertrophy. Explain the contributions made by adipokines (leptin, adiponectin and inflammatory cytokines) to insulin resistance, hypertension, cardiovascular disease, and cancer.