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1 Why Can t I Just Take a Pill to Lose Weight?

2 Topics 1. What is leptin? 2. How does leptin regulate weight homeostasis? 3. Why can leptin work in mice? 4. Why can t leptin work in human? 5. Some other proteins about weight control. 6. Other methods about losing weight.

3 What is leptin?

4 Obesity Occurs due to an imbalance between energy intake and expenditure, resulting in a net increase in the storage of body energy primarily as fat. Often associated with other various diseases and risks, such as diabetes, articular problems and increased surgical risk.

5 Adipocytes The traditional role attributed to adipose tissue is energy storage, fatty acid being released when fuel is required. Adipose tissue performs complex metabolic and endocrine functions. The hormone derived from adipocytes: leptin and adiponectin.

6 Leptin The product of ob gene. from the Greek word, leptos, meaning thin 167 a.a protein, 16 KDa 1950, a genetic defect that proceeds in massive obesity was identified in inbred obese mice. Ingalls et al.

7 Leptin 1973, parabiosis experiments: cross-circulation. Diabetologia 1973; 9: , cloning of the mouse ob gene and its human homologue. Nature 1994; 372: , identified leptin defective receptor of the db/db mouse. Lee et al.

8 Leptin Concentrations are higher in women when compared with men. (Caro et al. 1996). Slowly declines during aging. The reduction is higher in women than in men. (Isidori et al. 2000)

9 Leptin receptor single-transmembranedomain receptor. leptin receptors are found not only in the brain. Three forms: long, short, and very short. Signal transduction BBB

10 Leptin Provide the brain with the information about fat storage of body. Feedback mechanism can function as a lipostat.

11 How does leptin regulate weight homeostasis?

12 Leptin v.s Insulin Round 1 Leptin: 1. Regulation of food intake 2. Energy balance 3. Inhibition of insulin secretion 4. Stimulation of lipolysis in adipocytes 5. Increasing of fatty acids synthesis in liver Insulin: 1. Enhance glucose diposal 2. Storage and oxidation in glucose homeostasis 3. Be an anabolic hormone

13 Leptin v.s Insulin Round 2 Nature 404, (06 Apr 2000) Insight

14 Leptin v.s Mechanism Round 3 Nature 404, (06 Apr 2000) Insight

15 Leptin v.s CNS Round 4 Nature 404, (06 Apr 2000) Insight

16 Leptin v.s Signal transduction Final Round Nature 404, (06 Apr 2000) Insight

17 Why can leptin work in mice?

18 Leptin Leptin receptor (LR), a single membrane-spanning receptor Gene expression for LR was strong in the arcuate nucleus (ARC), ventromedial nucleus (VMH or VMN), dorsomedial, paraventricular and ventral premammilary nuclei of the hypothalamus and moderate in the lateral hypothalamus (LH).

19 The VMH, one of the largest nuclei of the hypothalamus, was long considered to be a satiety center Stimulation of the VMH inhibits feeding, whereas a lesion in this region causes overeating and weight gain. Recent studies have shown high abundance of leptin receptors (long form: Ob-Rb) in neurones of the VMH, and evidence indicates that this region may be an important target for circulating leptin. The ARC and LH are feeding centers

20 the ARC contains numerous neuropeptide Y (NPY)-containing neurons and fibers. NPY is involved in the stimulation of food intake and the regulation of energy balance. Leptin exerts its anorexic effects via a coordinated response that combines inhibition of NPY with stimulation of CRH-producing neurons.

21 The present study first demonstrates that leptin inhibits Lg induced increase in [Ca 2+ ] i in the neurons of the feeding centers, ARC and LH, and increases [Ca 2+ ] i in the neurons of the satiety center, VMH.

22 Leptin administration directly into the brain of fasted rats should increase hypothalamic expression of CRH and decrease expression of NPY, leading to an attenuated feeding response. Since CRH acts in this brain area to inhibit food intake and to increase energy expenditure.

23 Leptin therefore appears to stimulate the POMC neurones, with the increase in POMC expression presumably resulting in elevated -MSH production and release and thus reduced food intake. Leptin also increases CART expression and leads to reduce food intake

24 Corticotropin-releasing hormone (CRH): PVN decreases food intake and body weight; increases sympathetic nervous system activity, thereby increasing thermogenesis; energy expenditure, and lipolysis. Cocaine- and amphetamine-regulated transcript (CART): ARC, PVN, DMH, LHA decreases food intake and body weight Pro-opiomelanocortin (POMC ACTH & -MSH ) ARC, pituitary gland, NTS lipolysis ; decreases food intake and body weight ;immune function ; pigment formation ; nervous system function

25 Leptin VMH (satiety center) ARC,LH (Feeding center) Fat cell mass NPY ; CRH,POMC( -MSH),CART Food intake Anorexia

26 Why can t leptin work in human?

27 ? (WHO) International Obesity Task Force

28 :1995 OB gene : : 30% :

29 risk (at risk) 1 mild 2 severe 3 BMI < ~ ~29.9 >30 30~ ~39.9 >40

30 Human leptin Humans fat cells also manufacture a leptin (a protein of 167 amino acids) Mutations in the gene for leptin, or in its receptor, are rarely found in obese people.

32 The rare cases homozygous for mutations (frameshift in one family, missense in the other) in their leptin gene. ~ ob/ob mice homozygous for mutations in their leptin receptor gene. ~db/db mice heterozygous (one mutant and one normal) for their leptin genes.

33 Recombinant Human Leptin 1999, a year-long trial of recombinant leptin in a 9-yearold girl who is homozygous for a frameshift mutation in her leptin genes

34 The findings She began the trial weighing 208 pounds (94.4 kg), of which 123 lbs (55.9 kg) was fat. She had lost 36 lbs (16.4 kg), most of it fat. Her appetite and thus food intake had decreased. Her immune system made antileptin antibodies.

35 /27 Journal of American Medical Association Leptin 73, 24 35, 20,

36 Leptin - Can Obese Mice Lead to Lean People? (receptor) leptin leptin leptin

37 Result leptin, OB gene mutant leptin

38 Some other proteins about weight control

39 Cholecystokinin(CCK) Produced by I-cell Pancreatic enzyme secretion Bile secretion and contraction of gall bladder Inhibition of gastric emptying Inhibition of food intake

40 Cholecystokinin(CCK) Daily CCK injection enhances reduction of body weight by chronic intracerebroventricular leptin infusion. Ebenezer IS. Eur J Pharmacol 2002 Apr 19;441(1-2):79-82

41 Neuropeptide Y(NPY) secretion of the NPY peptide in the hypothalamus increas during active depletion of body fat stores and /or reduced leptin/insulin signalling to the brain Injection of NPY into the hypothalamus increases food intake High NPY levels are correlated with Leptin NPY-knockout can reduce obesity in leptin deficient mice.

42 Proopiomelanocortin (POMC) Precursor generated in neurons of the hypothalamus activation melanocortin-4 receptor (MC4R)

43 Ghrelin made by stomach cells endogenous ligand for growth hormone seretagogue receptor (GHS-Rs) regulation of food intake and body weight

45 Peptide YY(PYY) distal gut hormone feedback inhibition of gastric acid secretion, gastrointestinal motility, and pancreatic enzyme output In humans, infusion of normal postprandial concentrations of PYY(3-36) significantly decreases appetite and reduces food intake by 33% over 24 h.

46 PYY

47 Agouti-Related Protein (AGRP) Present in the hypothalamus potent antagonist of MC3-R and MC4-R regulate feeding behavior and body weight

49 Peptide YY 3-36 (PYY) released from the gastrointestinal tract tract postprandially in proportion to the calorie content of a meal inhibits electrical activity of NPY nerve terminals activating adjacent pro-opiomelanocortin (POMC) neurons

50 Insulin Secretion from islet cells of the endocrine pancreas. insulin has peripheral anabolic effects that increase lipid synthesis and storage. A misconception that insulin causes weight gain and obesity has evolved.

51 Insulin in CNS CNS neurons do not produce insulin. transported into the brain by a receptormediated mechanism. occurring over a period of hours after circulating insulin concentrations increase. insulin is the long-term regulation of body adiposity rather than as a short-term satiety signal.

52 Insulin suppress food intake 1979, Woods, Porte and colleagues: infusion of insulin into the cerebral ventricles inhibition of food intake and body weight loss. 1995, Sipols AJ, Baskin DG, Schwartz MW: insulin-deficient diabetic rats (marked increase of food intake) diabetic hyperphagia was reduced by 50%

53 In addition to inhibiting food intake, insulin increases sympathetic neural activity and energy expenditure. Vollenweider P, J Clin Invest 93: , & Diamond P, LeBlanc J. Am J Physiol 254:E625 E632, Thus, insulin can modulate energy balance by inhibiting food intake and by increasing thermogenesis.

54 Other methods about losing weight

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University of Science and Technology of China A dissertation for master s degree Transdermal Delivery of Gut Hormone PYY3-36 for the treatment of Obes

中国科学技术大学硕士学位论文肠激素 PYY3-36 透皮给药治疗肥胖症的研究作者姓名 : 学科专业 : 导师姓名 : 完成时间 : 陈敏细胞生物学温龙平教授二一年八月三十一日 University of Science and Technology of China A dissertation