Hormonal Regulation of Appetite and Satiety PDF

1 Hormonal regulation of appetite and satiety Dr Li Kang ([email protected])  2 Learning objectives Describe the role of the hypothalamus in metabolic homeostasis Describe how neuropeptides and...

1 Hormonal regulation of appetite and satiety Dr Li Kang ([email protected])  2 Learning objectives Describe the role of the hypothalamus in metabolic homeostasis Describe how neuropeptides and hormones are involved in the hypothalamic control of energy intake and body weight Describe animal models of obesity and their relation to human obesity 2  3 Obesity – a disease of the brain? Why is it difficult to lose weight once gained? Increased body fat alters brain function Long-term obesity leads to brain re-programming Your brain views extra weight (fat) as the norm and dieting is a threat to survival. i.e. defends new weight 3  4 Central Control of Energy Intake and Body Weight CNS influences energy balance and body weight by: 1) Behaviour – feeding and physical activity 2) ANS activity – regulates energy expenditure 3) Neuroendocrine system – secretion of hormones Integration of these determines the final output feeding behaviour The BRAIN and specifically the HYPOTHALAMUS integrate these signals 4  5 Part 1 The hypothalamus Neuropeptides, hormones and central signals  6 Hypothalamus and obesity Body weight stable over lengthy periods of time Energy balance controlled by feedback loop(s) – maintain constancy of energy stores 6  Finding balance 7 Aim: ensure the body has enough energy both now, and in times of starvation Methods: Store energy when in surplus, use stores in starvation, promote energy intake when stores are low, discourage food intake when stores are full. Orexigenic Anorexigenic Food intake ↑ ↓ Energy storage ↓ ↑ Energy expenditure ↓ ↑  8 Hypothalamic regulation - Appetite and Satiety Feedback regulation Signals produced in response to body nutritional status Signals detected by the hypothalamus Act to modulate food intake and energy expenditure Short-term processes regulate meal initiation, termination and inter-meal frequency Body weight and food intake are also regulated by long- term processes e.g., adiposity signals. What are these signals ? 8  Neuropeptides and Obesity 9 In the last decades there has been an explosion of information regarding the understanding of hypothalamic regulation of food intake and body weight. Driven by the discovery of numerous regulatory peptide molecules: produced and released intrinsically in the hypothalamus produced and secreted peripherally and access hypothalamus Orexigenic Anorexigenic e.g NPY LEPTIN* GALANIN INSULIN* MCH a-MSH OREXINS CART AGOUTI GLP-1 GHRELIN TRH ENDOCANNABINOIDS CRH PYY3-36 *Arguably not neuropeptides  Melanocortins - αMSH 10 αMSH- α melanocyte stimulating hormone formed by sequential cleavages of the proopiomelanocortin (POMC) precursor polypeptide POMC gene expression is reduced on fasting and increased following attainment of a positive energy balance αMSH levels are high in the hypothalamus and this peptide inhibits food intake. (Anorexigenic) Melanocortin receptor subtypes - MC-3 & MC-4 are mainly expressed in brain. Synthetic agonists and antagonists to these suppress and enhance food intake respectively. Deletion of MC-4 or MC-3 receptor produces obesity in mice.  Neuropeptides and Obesity 11 In the last 30 years there has been an explosion of information regarding the understanding of hypothalamic regulation of food intake and body weight. Driven by the discovery of numerous regulatory peptide molecules: produced and released intrinsically in the hypothalamus produced and secreted peripherally and access hypothalamus, Orexigenic Anorexigenic e.g NPY LEPTIN* GALANIN INSULIN* MCH a-MSH OREXINS CART AGOUTI GLP-1 GHRELIN TRH ENDOCANNABINOIDS CRH PYY3-36 *Arguably not neuropeptides  Neuropeptide Y (NPY) 12 NPY - a 36 aa peptide; one of the most abundant in the human brain. Significant number of NPY-containing neurons in the arcuate nucleus (ARC) Injection of NPY into hypothalamus potently stimulates food intake and reduces energy expenditure (orexigenic) Repeated administration of NPY leads to obesity NPY receptor antagonists attenuate feeding, reduce obesity Mice lacking NPY receptor subtypes, Y1 or Y5 pre-disposed to obesity  Agouti-related Protein (AgRP) 13 AgRP co-expresses with NPY in ARC neurons AgRP and Agouti (Ay) are antagonists to MC3 and MC4 receptors Intracerebroventricular (ICV) AgRP causes long lasting hyperphagia (Orexigenic)  Neuropeptides and Obesity 14 In the last 30 years there has been an explosion of information regarding the understanding of hypothalamic regulation of food intake and body weight. Driven by the discovery of numerous regulatory peptide molecules: produced and released intrinsically in the hypothalamus produced and secreted peripherally and access hypothalamus, Orexigenic Anorexigenic e.g NPY LEPTIN* GALANIN INSULIN* MCH a-MSH OREXINS CART AGOUTI GLP-1 GHRELIN TRH ENDOCANNABINOIDS CRH PYY3-36 *Arguably not neuropeptides 15  Adiposity signals - Leptin 16 Member of the cytokine family, 146 aa long, made & secreted from adipocytes Circulates in proportion to fat mass (adiposity) Specific transport system for leptin to enter brain High levels of leptin receptors (Ob-Rb) expressed on ARC hypothalamic neurons ICV leptin inhibits food intake and decreases body weight of rodents Neuron specific deletion of the leptin receptor (Ob-Rb) results in obesity  Biological Roles of leptin 17 Food intake/energy expenditure/fat deposition Peripheral glucose homeostasis/insulin sensitivity Maintenance of immune system Maintenance of reproductive system Angiogenesis Tumorigenesis Bone formation  18 Adiposity signals - Insulin Circulates in proportion to adiposity but secreted from the pancreas Transport system for insulin to enter brain High levels of insulin receptors expressed in hypothalamus most notably in the ARC ICV insulin inhibits food intake and decreases body weight of rodents Neuron specific deletion of the insulin receptor results in obesity NB. Peripheral actions of insulin are opposite 19  Neuropeptides and Obesity 20 In the last 30 years there has been an explosion of information regarding the understanding of hypothalamic regulation of food intake and body weight. Driven by the discovery of numerous regulatory peptide molecules: produced and released intrinsically in the hypothalamus produced and secreted peripherally and access hypothalamus, Orexigenic Anorexigenic e.g NPY LEPTIN* GALANIN INSULIN* MCH a-MSH OREXINS CART AGOUTI GLP-1 GHRELIN TRH ENDOCANNABINOIDS CRH PYY3-36 *Arguably not neuropeptides 21  22 Satiety Signals Site of secretion Stimulus Action Cholecystokinin Enteroendocrine cells of Released in proportion to lipids Signals via sensory nerves to hindbrain and (CCK) duodenum and jejumen and proteins in meal. stimulates hindbrain directly (nucleus of solitary tract – NTS) Peptide YY Endocrine mucosal L-cells Levels increase rapidly post- Inhibits gastric motility, slows emptying and (PYY 3-36) of G-I tract prandially reduces food intake (Hypothalamus) Glucagon-like L cells of G-I tract Levels increase in response to Inhibits gastric emptying and reduces food peptide 1 (Product of pro-glucagon food ingestion intake (Hypothalamus and NTS) (GLP-1) gene) Oxyntomodulin Oxyntic and L-cells of small Released after meal Acts to suppress appetite – mechanism and site (OXM) intestine (produce of pro- unclear. glucagon gene) Obestatin cells lining stomach/ small Release in response to ingestion Reduces food intake (may act to antagonise intestine (peptide from ghrelin). gene encoding ghrelin) Ghrelin Octanoylated peptide. Levels increase before and Stimulates food intake (Hypo) and decreases Produced by oxyntic cells in decrease after meals. Levels fat utilization by acting on the growth hormone stomach raised by fasting and secretagogue receptor (GHSR). hypoglycaemia. 22  23 Part 2 Models of Obesity  24 Monogenic Obesity – rodents lead the way Rodent models of obesity play key role in elucidating neural pathways Spontaneous monogenic mutations in mouse strains resulting in obesity These genes crucial elements of physiological pathways for energy balance control Ob/Ob mouse db/db mouse Similar phenotype to Ob mouse but leptin insensitive Ob mouse with normal littermate db gene codes for LEPTIN RECEPTOR (Ob-R) Ob-R – single gene product with several alternatively Spontaneous mutation resulting in obesity spliced variants Ob gene cloned in 1994 Long cytoplasmic domain form of receptor (Ob-Rb) Discovery of hormone LEPTIN highly expressed in hypothalamus and point mutation Reduced leptin mimics starvation – unrestrained appetite prevents formation of Ob-Rb leading to obesity 24  Agouti and obesity 25 Gene encodes a small protein - AGOUTI - natural; antagonist of the melanocortin 1 (MC-1) receptor in melanocytes - responsible for hair colour Ay (Agouti yellow) mutation results in gene rearrangement causing ubiquitous ectopic expression and a yellow coat colour Ay mutation leads to obesity Ay also antagonist for hypothalamic MC-4 receptor – this is the cause of obesity in this mouse model  26 Agouti (Ay) - yellow mouse mutant (lethal in homozygotes) Heterozygotes - yellow coat colour obese hyperglycaemic insulin resistant leptin resistant Ay abnormally expressed in the brain mimics neuronal homolog AgRP  Mouse models of obesity 27 Name Gene Biochemistry Physiology Zucker fa/fa rat Ob-R ↓ functional leptin Obesity receptor Leptin resistance db/db mouse Ob-R ↓ functional leptin Obesity receptor Leptin resistance Ob/Ob mouse Ob ↓ leptin Obesity fat/fat mouse CPE Loss of Function Obesity (carboxypeptidase CPE E) ↓ α-MSH CPE: an enzyme essential for the maturation of hormones including insulin and POMC Rodent mutations in signalling pathway 28 Second-order Adipose ARC neurons aMSH MC4-R Leptin POMC CPE AgRP Ob-Rb db Ob fat Ay fa  29 Parallels between mouse models and humans Deficiency / Species Mouse Human Leptin Obese Obese Leptin receptor Obese Obese POMC Obese Obese MC4-R Obese Obese  Searching for human obesity genes 30 Monogenic causes for obesity are rare Ob mutations extremely rare- those without detectable leptin extremely obese Truncated leptin receptor (Ob-R) reported Loss of Function POMC (e.g. ↓ αMSH) No CPE mutations, mutations in PC1 (another POMC processing protein) linked to obesity More common (