Brain Circuits Driving Appetite
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To learn more and watch the webinar, visit: https://insidescientific.com/webinar/brain-circuits-driving-appetite-obesity-2020 In many western countries, nearly a quarter of us meet the criteria for clinical obesity and more than half of us are overweight. This is a medical concern because obesity is a serious risk factor for many major chronic illnesses, such as heart disease, type 2 diabetes and cancer, and as a result, obesity is associated with reduced lifespan by almost a decade. The rapid escalation in the prevalence of obesity and the paucity of obesity medications underscores the necessity of an understanding of the basic neurobiology underlying body weight. During this webinar, Professor Heisler will discuss brain circuits that are the main known controllers of body weight, such as those activated by the adipocyte hormone leptin. She will review how our genes impact our waistline and will discuss crucial genes such as those in the melanocortin system. Professor Heisler will discuss how obesity medications capitalize on this basic neurobiology to promote satiety, reduce hunger and decrease body weight. Key discussion topics include: – Gut to brain communication – Key brain chemicals mediating satiety – Key brain chemicals controlling hunger
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Brain Circuits Driving Appetite
- 1. Lora Heisler, PhD Chair in Human Nutrition Rowett Institute University of Aberdeen Institute of Medical Sciences Obesity Series 2020 Brain Circuits Driving Appetite
- 2. Lora Heisler, PhD discusses the unique brain circuits controlling body weight, how our genes impact our waistline and how obesity medications leverage basic neurobiology to reduce hunger and decrease body weight. Brain Circuits Driving Appetite
- 3. Thank you to our partners and sponsors that have helped make this webinar series possible! Partners & Sponsors
- 4. Lora Heisler, PhD Chair in Human Nutrition Rowett Institute University of Aberdeen Institute of Medical Sciences Brain Circuits Driving Appetite Copyright 2020 L. Heisler and InsideScientific. All Rights Reserved. CLICK HERE to learn more and watch the webinar
- 5. Brain circuits driving appetite Lora Heisler, PhD
- 6. World map of obesity Adapted from World Health Organization, 2016 Prevalence From http://www.who.int/gho/ncd/risk_factors/overweight/en/ Accessed June 2, 2018 In the USA, the incidence of obesity has increased 4-fold over the last 20 years The incidence of childhood obesity is increasing at the fastest rate USA expenditure > $147 bn each year to treat obesity and its related conditions
- 7. Current UK rates of overweight and obesity Adapted gov.uk
- 8. Increased risk of disease Defining obesity: body mass index
- 9. UK adults are obese Type 2 Diabetes Heart Disease Cancer Gout Fatty liver disease Gall bladder disease Phlebitis Pancreatitis Obesity: A global healthcare challenge of the 21st century
- 10. Obesity: now leading cause of some forms of cancer
- 12. Intake Expenditure< Intake Expenditure < Basal metabolism Physical activity Thermogenesis Calories Intake Expenditure = Neutral energy state Stable weight Negative energy state Weight loss Positive energy state Weight gain The energy balance equation
- 13. 180 mins walking 35 mins cycling 40 mins swimming 45 mins gardening 35 mins dancing 60 mins yoga 540 kcal 260 kcal 211 kcal 139 kcal 134 kcal 92 kcal 215 g Big Mac 58 g Mars Bar 200 g Yogurt 330 ml Coca-Cola 25 g Chips 200 ml Semi-Skim Milk The energy balance equation: Diet and Exercise CLICK HERE to learn more and watch the webinar
- 14. Food intake Factors influencing obesity Obesity Exercise Metabolic rate Culture Genetic susceptibility Monogenic syndromes GENES DIETMETABOLISM
- 15. Food Intake – central Neurotransmitters: 5-HT, adrenaline, noradrenaline, histamine Neuropeptides: POMC, AgRP, NPY, Orexin, CRH Cannibinoids, BDNF Factors influencing obesity Basal metabolism Physical activity Thermogenesis Calories - Thermogenesis Thyroid hormones β-adrenergic agonists Uncoupling proteins Fat absorption Lipase inhibitors Fatty acid transporters Physical activity Fat metabolism Adipocyte differentiation Adipogenesis Apoptosis Food Intake – peripheral GI peptides: CCK, GLP1, PYY, Ghrelin Pancreatic peptides: Insulin, glucagon, amylin Adipokines: Leptin, adiponectin
- 16. Leptin: Hormone produced by fat (adipose tissue) When leptin levels rise, appetite is suppressed. When body fat decreases or during fasting, leptin levels fall and appetite increases Leptin
- 17. 1949 ob/ob mouse Spontaneous recessive mutant Three times the weight of control mice Ate twice the amount of food as control mice 1994 Cloning of Ob gene Circulating hormone called leptin (Greek for ‘thin’) Produced by adipocytes Anorectic 1997 Human leptin deficiency Almost non-existent serum levels of leptin Children with profound obesity Homozygous frameshift mutation 1999 Leptin replacement therapy Leptin deficient children treated with recombinant leptin Significant decrease in food intake and body weight Leptin CLICK HERE to learn more and watch the webinar
- 18. 1996 Cloning of ObR/LepR gene Only Receptor for leptin Receptor expressed within the brain modulates appetite 1966 db/db mouse Spontaneous recessive mutant Three times the weight of control mice Suffer from severe diabetes 1997 Human LepR variation Polymorphisms in LepR are associated with increased body weight 1998 Human LepR mutation Very rare Children with profound obesity and high levels of serum leptin No cure Leptin Receptor CLICK HERE to learn more and watch the webinar
- 19. Leptin Hormone released from adipocytes Anorectic peptide Genetic mutation in mice and humans causes profound hyperphagia and obesity Leptin replacement can ameliorate these phenotypes However, leptin is not a useful treatment in common obesity because of elevated leptin levels Leptin receptor Cytokine –family receptor Genetic mutation in mice and humans causes hyperphagia and obesity Only centrally expressed LepRb is involved in energy homeostasis Elevated leptin levels in obesity promote leptin resistance at LepR Leptin anorectic action Leptin drug discovery is centred around decreasing leptin resistance Leptin Summary
- 20. Harness inverse relationship between leptin and food intake Can leptin treatment improve obesity? Research attempting to develop drugs to increase leptin sensitivity
- 21. Food Intake – central Neurotransmitters: 5-HT, adrenaline, noradrenaline, histamine Neuropeptides: POMC, AgRP, NPY, Orexin, CRH Cannibinoids, BDNF Factors influencing obesity Basal metabolism Physical activity Thermogenesis Calories - Thermogenesis Thyroid hormones β-adrenergic agonists Uncoupling proteins Fat absorption Lipase inhibitors Fatty acid transporters Physical activity Fat metabolism Adipocyte differentiation Adipogenesis Apoptosis Food Intake – peripheral GI peptides: CCK, GLP1, PYY, Ghrelin Pancreatic peptides: Insulin, glucagon, amylin Adipokines: Leptin, adiponectin
- 22. hunger hunger POMC AGRP- -+ Orexigenic MCR antagonist/inverse agonist Expressed in ARC Adult knockout mice lean & hypophagic Anorectic MCR agonists Expressed in ARC & NTS Knockout mice are obese & hyperphagic Adapted from Yeo and Heisler, Nature Neurosci 2012 Garfield et al., Trends in Endo and Metab 2009 Melanocortin: Principal Energy Balance Mediator MC4R Gs MC3R Gs
- 23. Melanocortin: Principal Energy Balance Mediator CLICK HERE to learn more and watch the webinar
- 24. POMC deficiency causes obesity
- 25. Body weight Food intake Melanocortin4 receptor deficiency causes obesity in mice
- 26. In 1998, two groups reported heterozygous mutations in the MC4R in humans that were associated with dominantly inherited obesity. Heterozygous mutations in MC4R have been reported in obese humans from various ethnic groups and represent the commonest known monogenic cause of human obesity (5–6% of severely obese subjects). MC4R deficient Control Melanocortin4 receptor deficiency causes obesity in people
- 27. Translation into obesity medication – MC4R agonist Setmelanotide to treat rare genetic obesity
- 28. Food Intake – central Neurotransmitters: 5-HT, adrenaline, noradrenaline, histamine Neuropeptides: POMC, AgRP, NPY, Orexin, CRH Cannibinoids, BDNF Factors influencing obesity Basal metabolism Physical activity Thermogenesis Calories - Thermogenesis Thyroid hormones β-adrenergic agonists Uncoupling proteins Fat absorption Lipase inhibitors Fatty acid transporters Physical activity Fat metabolism Adipocyte differentiation Adipogenesis Apoptosis Food Intake – peripheral GI peptides: CCK, GLP1, PYY, Ghrelin Pancreatic peptides: Insulin, glucagon, amylin Adipokines: Leptin, adiponectin
- 29. Discovery of Serotonin AKA 5-HT: 1948 Maurice M. Rapport Arda Green Irvine Page
- 30. Like leptin, inverse relationship between 5-HT and food intake 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT
- 31. Harness inverse relationship between 5-HT and food intake Can 5-HT medications improve obesity?
- 32. Fluoxetine 10 mg/kg *** ** ** 2 4 7 10 0 20 40 80 100 60 83 5 6 9 Pre-Drug Drug Post-Drug WEEKS BodyWeightGain(g) Saline *** *** * * *** Adapted from Heisler et al., Pharm Biochem Beh, 1997 Prozac reduces food intake and body weight 2 4 7 10 0 20 40 80 100 60 83 5 6 9 Pre-Drug Drug Post-Drug WEEKS KcalIntake *** *** ** **
- 33. 5-HT medications approved for obesity
- 34. D-fenfluramine stimulates 5-HT release and blocks 5-HT reuptake Presynaptic Nerve Terminal Postsynaptic Nerve Terminal d-fenfluramine 5-HT 5-HT Receptor
- 35. D-fenfluramine removed from clinic
- 36. How do 5-HT medications improve obesity? Which 5-HT receptor?
- 37. Adapted from Lam & Heisler, Expert Reviews in Molecular Medicine, 2007 5-HT Receptor Families
- 38. The 5-HT2CReceptor mediates 5-HT’s effects on appetite & body weight (Adapted from Tecott, et al. Nature 1995) Wild Type 5-HT2CR KO 39-43 wk Food Intake 12-14 wk Foodintake(g) 2 0 4 3 1 5 * * Age (weeks) Age (weeks) 4 12 24 32 0 15 20 35 40 30 288 16 20 Body Weight 25 10 * * **** BodyWeight(g)
- 39. Designer Receptors exclusively activated by Designer Drugs (DREADD) 1 2 4 3 1. Stereotaxic DR injection of AAV-DREADD Gq into Tph2-iCre mice 2. DREADD Gq expression in DR 5-HT neurons 3. Systemic administration of designer drug CNO 4. Real-time activation of 5-HT DR neurons Increased neuronal activity GPCR Neurotransmitter Cell membrane Protein engineering Neurotransmitter Designer drug DREADD Increased neuronal activity (e.g. Gq) **
- 40. How do 5-HT medications improve obesity? Which 5-HT receptor? 5-HT2CR Regulating the activity of which cells?
- 41. Proposed Model: 5-HT obesity medication therapeutic effect • D-fenfluramine stimulates the release of 5-HT from the dorsal raphe (DR) into the hypothalamic arcuate nucleus (ARC) • 5-HT activates Gq 5-HT2CRs expressed with POMC, causing the release of α-MSH • α-MSH binds to MC4-Rs to reduce food intake and body weight Dorsal Raphe 5-HT 5-HT2CR α-MSH POMC ARC d-fenfluramine 5-HT
- 42. D-fenfluramine reduces appetite by activating POMC neurons
- 43. Clinical significance of this finding – lorcaserin (now withdrawn in USA) 5-HT2CR agonist CLICK HERE to learn more and watch the webinar
- 44. How does lorcaserin improve obesity? require melanocortin Does lorcaserin also pathways?
- 45. Circuit through which 5-HT2CR medications reduce appetite Lorcaserin α-MSH 5-HT2CR POMC CLICK HERE to learn more and watch the webinar
- 46. α-MSH POMC 5-HT2CR X 4hfoodintake(%sal) 60 0 200 100 40 80 20 *MC4-R X Burke et al. Molecular Metabolism, 2017 Lorcaserin reduces appetite by activating POMC neurons
- 47. α-MSH POMC 5-HT2CR X Mc4r WT allele HinDIII NotIATG+1 disrupted, null allele ATGHinDIII NotI loxP loxP Mc4rTB=Stop +1 3hfoodintake(g) 1.0 0.0 2.0 1.5 Sal 0.5 Lorc WT * Sal Lorc Mc4r null MC4-R Burke et al. Molecular Metabolism, 2017 Lorcaserin reduces appetite by activating a POMC to MC4R circuit
- 48. 5-HT obesity medication therapeutic effect • D-fenfluramine stimulates the release of 5-HT from the dorsal raphe (DR) into the hypothalamic arcuate nucleus (ARC) • 5-HT activates Gq 5-HT2CRs expressed with POMC, causing the release of α-MSH Dorsal Raphe 5-HT 5-HT2CR α-MSH POMC MC4-R ARC Lorcaserin d-fenfluramine 5-HT Lorcaserin
- 49. • Lorcaserin bypasses 5-HT and activates Gq 5-HT2CRs expressed with POMC, also causes the release of α-MSH • α-MSH binds to MC4-Rs to reduce food intake and body weight Dorsal Raphe 5-HT 5-HT2CR MC4-R α-MSH POMC ARC Lorcaserin d-fenfluramine 5-HT Lorcaserin 5-HT obesity medication therapeutic effect • D-fenfluramine stimulates the release of 5-HT from the dorsal raphe (DR) into the hypothalamic arcuate nucleus (ARC) • 5-HT activates Gq 5-HT2CRs expressed with POMC, causing the release of α-MSH
- 50. Overweight and obesity are now the norm in many countries, such as the UK and USA and this is having a negative impact on health (e.g. increasing susceptibility to major disease and shortening lifespan). Most people can improve their health with diet and exercise alone. But for some, other treatment options are a necessity. The brain is the master coordinator of energy homeostasis because it integrates signals and factors from all over the brain and body. Insights into the control of appetite have been gained through genetic and drug studies in mice and this has led to new medications now in human use. It is essential that the underpinnings of body weight are discovered to aid in the prevention and treatment of obesity. Summary CLICK HERE to learn more and watch the webinar
- 51. Thank you for participating! CLICK HERE to learn more and watch the webinar Lora Heisler, PhD Chair in Human Nutrition Rowett Institute University of Aberdeen Institute of Medical Sciences
Hinweis der Redaktion
- Welcome everyone to the very first webinar of Obesity 2020, a joint webinar series brought to you from InsideScientific and the American Physiological Society. This is Liam Sanio from InsideScientific and I’m very pleased to be your host for today’s event. Between now and December, we have a number of webinars lined up, all focused on the science being conducted by leading obesity researchers around the world. Today’s webinar is titled “Brain Circuits Driving Appetite” and will feature Professor Lora Heisler from the Rowett Institute at the University of Aberdeen in Scotland. Professor Heisler will discuss how our brain circuits control body weight, for example through the adipocyte hormone leptin. She will also review how our genes impact our waistline and how obesity medications capitalize on neurobiology to promote satiety, reduce hunger and decrease body weight.
- And now without any further ado, I’m very pleased to welcome Professor Lora Heisler. Lora, thanks so much for joining us today! --- Feel free to take it away whenever you’re ready.
- I’m sure everyone’s really looking forward to getting started, but first we’d like to acknowledge our partners at the APS and thank the sponsors of the webinar series for making it all possible.
- And now without any further ado, I’m very pleased to welcome Professor Lora Heisler. Lora, thanks so much for joining us today! --- Feel free to take it away whenever you’re ready.
- ** Replace mouse with a photo of a burger or ice cream
- Overweight and obesity are defined as excess calories stored as fat. The amount or degree of excess fat determines where an individual sits on the overwieght-obesity spectrum. So that tall men versus small women or teenagers can be compared, a body mass index was created that gives an estimate of the amount of fat, as determined by height and weight. You can find these online
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- Great, Thank you so much Lora all of your fantastic insights today, both in your presentation as well as the Q&A session. ========== Thank you everyone for joining us today to attend the webinar! Again, the slides and a recording of today’s webinar will be available soon at InsideScientific.com, so look out for an email regarding these resources in the near future. Finally, we invite you to please take a moment to let us know what you thought of the webinar on the survey to provide your feedback and let us know what webinar topics you’d like to see in the future. In closing, thank you again for taking part in this InsideScientific webinar produced in partnership with the American Physiological Society, and we look forward to having you with us again soon!