Obesity: controlling appetite ppt,Dr Madhushree Pahari

Obesity: hormones regulating appetite ,leptin,adiponectin,enteroendocrine hormone, appetite control signals,leptin melanocortin pathway,POMC

1. Obesity: Inspiration from The hormonal milieu Lenz A, Diamond Fb Presented by: Dr.Madhushree Pahari Postgraduate Trainee Dept.of Biochemistry IPGME&R Moderated by: Dr. Kasturi Mukherjee Assistant professor Dept. of biochemistry IPGME&R

2. INTRODUCTION Obesity is a complex disorder of appetite regulation and energy metabolism controlled by specific biological factors. It is characterized by excess body fat. Globally, the WORLD HEALTH ORGANIZATION estimates that a billion adults have a body mass index greater than 25 kg/m2 and 300 million are obese with BMI over 30kg/m2. Obesity has reached epidemic proportions throughout the world and poses significant health and economic burden to both developed and developing societies that, the WORLD HEALTH ORGANISATION has outlined obesity as “a world epidemic disease”.

3. Hormones regulating appetite Adipocyte derived hormones: leptin, adiponectin, and visfatin . Enteroendocrine hormones: ghrelin, obestatin , cholecystokinin, glucagon-like peptide-1, polypeptide yy , glucose-dependent insulinotropic polypeptide, oxyntomodulin and insulin.

4. Appetite control signals Transmitted by vagal inputs, adipocyte-derived hormones and enteroendocrine hormones. These signals converge in two discrete locations in the central nervous system[CNS], the brainstem and the hypothalamus. The brainstem nuclei consist nucleus of tractus solitarius which receives the vagal afferent signals from gut receptors and the area postrema which has an incomplete blood-brain barrier responds to circulating factors. Hypothalamic arcuate nucleus receives adipokines and enteroendocrine signals.

5. Appetite control signals(contd.) Hypothalamic arcuate nucleus contain orexigenic neuropeptide y [NPY] and agouti-related peptide [AGRP] producing neurons, as well as anorexigenic pro-opiomelanocortin[POMC],cocaine and amphetamine receptor transcript [CART] peptide producing neurones. NPY,AGRP,POMC and CART peptides interact with receptors in hypothalamic nuclei.NPY stimulates Y1 and Y5 receptors,AGRP inhibits melanocortin [MC] 4 and MC5 receptors where POMC stimulates MC4 and MC5 receptors.CART receptors has not yet been characterized.

6. Appetite controlling hormones

7. Leptin Released from adipocytes. Direct proportion to total body fat mass. Actively transported into the CNS. Exerts anorexigenic effects. Increases sympathetic tone and energy expenditure Acts via JAK-STAT pathways.

8. Hypothalamic leptin-melanocortin pathway

9. Leptin induced JAK/STAT signaling

10. Leptin resistance State of hyperleptinemia. Lack of response to the hormone. Classified as central leptin resistance and peripheral leptin resistance

11. Adiponectin an anti-inflammatory adipokine  Matrix like protein Expressed abundantly in subcutaneous fat Reduced in obesity Action mediated by fuel sensing enzyme AMPK.

12. AMPK:a highly conserved master regulator of metabolism Net effect of adiponectin through AMPK pathway Increased insulin sensitivity, Decreased plasma glucose, Decreased plasma triglycerides, Decreased hepatic steatosis.

13. Visfatin Adipokine with Insulin-like metabolic actions produced by the intra-abdominal adipose tissue Stimulating glucose uptake by fat and muscle cells Inhibiting glucose release from hepatocytes Share similar affinity for insulin receptor It activates the IRS-PI3K-MAPK signaling pathway Visfatin is increased in obese children and adolescents

14. Enteroendocrine Hormone:Ghrelin often called as "hunger hormone” Secreted by the fundic oxyntic glands of the stomach Acts centrally by diffusion and active transport across blood-brain barrier Ghrelin and synthetic ghrelin mimetics increase body weight and fat mass by triggering receptors in the arcuate nucleus that include neuropeptide Y (NPY) and agouti-related protein ( AgRP ) neurons that initiate appetite.

15. Cholecystokynin hormone secreted by the I-cells of the upper small intestine Its secretion stimulated by the introduction of hydrochloric acid, amino acids, or fatty acids into the stomach or duodenum reduces food intake and modulates vagal afferent neurons Acts via CCK1 receptors in the gut,CCK2 receptors in the CNS Suppresses appetite,induces gallbladder contraction,increases intestinal motility,stimulates pancreatic enzymes and gastric acid secretion.

16. Polypeptide yy appetite suppressing gut hormone secreted from L-cells of the small intestine. Low levels of PYY have been associated with higher BMI and obesity increases satiety, inhibits gastrointestinal motility, inhibits pancreatic hormone secretion, and decreases food intake

17. Glucagon-like peptide-1 produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon encourages the release of insulin from the pancreas Evidence suggests that the action or effect of GLP-1 may be impaired in obese subjects,GLP-1 impairment increases gastric emptying and decreases satiety signalling seen in obesity.

18. Insulin produced by beta cells of the pancreatic islets Peripherally adipogenic but centrally appetite suppressive Insulin receptors concentrated in hypothalamus, hippocampus and cortex Can Cross blood brain barrier Acts via phosphtidyl inositol kinase pathways

19. Glucose dependent insulinotropic polypeptide Released from k cell in upper small intestine in response to nutrients specially fat Effects mediated by GIP receptors GIP increased in obesity Oxyntomodulin Released from L cell of small intestine In response to fat Acts at GLP 1 receptors

20. Early programming of energy regulation During prenatal hypothalamic development,extending into the early postnatal period leptin programs synaptic plasticity and neurotrophic growth Leptin gene or receptor mutation in individuals have an excessive appetite and weight gain by 3 months of age Ghrelin plays a developmental role in fetal growth and may programme appetite and feeding behaviour in infancy that could contribute to later onset of excess body fat

21. Early programming of energy regulation ( contd ). Lower cord ghrelin levels are associated with slower weight gain from birth to 3 months of age in term infants Exclusively breast-fed or formula-fed infants had lower ghrelin levels than those receiving solid foods. Gender differences in Adiponectin appear during the progression of puberty, lower concentrations in healthy lean males compared with female adolescents

22. Endocrine glands Excess glucocorticoids results in hyperphagia and increased centripetal obesity Hyperthyroid individuals experience weight loss despite increased appetite Triiodothyronine crossing the blood-brain barrier directly stimulate feeding independent of alteration in energy expenditure TRH promotes vagal cholinergic mediated stomach motility and secretion

23. conclusion