Neurophysiology and pharmacology of obesity

Transcription

1 How your brain controls body weight Neurophysiology and pharmacology of obesity Michael Cowley Head of Department of Physiology ANZMOSS, September, 2018, Melbourne.

2 Michael is a consultant to NovoNordisk and inova Research Support from NovoNordisk

3

4 70% OF AUSTRALIANS ARE OBESE OR OVERWEIGHT risks of heart disease risks of vascular disease risks of diabetes Significant, and rising, economic and social burden

5 Medical Complications of Obesity Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Gall bladder disease Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Osteoarthritis Skin Gout Idiopathic intracranial hypertension Stroke Cataracts Coronary heart disease Diabetes Dyslipidemia Hypertension Severe pancreatitis Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Phlebitis venous stasis

6 What are the neural mechanisms of energy balance? Input Output Input = food intake Output = physical activity basal metabolism adaptive thermogenesis Energy Homeostasis

7 Fat or Thin, Energy is Homeostatically Controlled Food Restriction MC4 R KO mice Normal mice

8 Short and Long Term Weight Regulation Weight gain Counter regulation Usual weight Weight loss Counter regulation

9 Response to Under or Overfeeding

10 Weight Regain after Behavior Modification Diet Program: n=16 studies 100 Safer. So. Med. J. 84:1470, % weight regain Duration of follow-up (years)

11 Body Weight and Fat Mass During and After Guru Fattening Session Pasquet, et al. Am J Clin Nutr : Guru Body weight Fat mass Time (months)

12 Leptin the pharmaceutical fix (at least for the ob/ob boy)

13 How does leptin work?

14 Mean (+/- SD) Observed minus Predicted Total Energy Expenditure (Kcal/day) Energy Expenditure Response to Weight Gain and Loss Leibel RL, et al. N Engl J Med 1995;332: % gain % of Initial Weight Initial Weight 10% loss % loss 70 Time Initial Weight 10% gain Can prevent this decrease with leptin replacement

15 The Hypothalamus Arcuate Nucleus is important POMC is important MC4 R is important 19

16 Metabolic Regulation Chain of Command Food intake Appetite LHA 2 nd order Metabolic Signal (leptin/insulin) ARC 1 st order VMH Energy Expenditure Thermogenesis

17 Leptin (ng/ml) Obesity is not associated with leptin deficiency Relationship between levels of leptin and fat in mice Relationship between levels of leptin and BMI in human r= p < r = p < Fat (g) Leptin (ng/ml) BMI Roth CL and Enriori PJ et al., Endogenous hyperleptinemia does not reduce appetite or increase energy expenditure in obese rodents and humans. This is termed leptin resistance. 22

18 We know the pathways through which leptin normally acts Have a detailed understanding of how body weight is regulated at a molecular level at a neuron level and on a brain circuit level Our circuit model explains how serotonin modulators regulate body weight Circuit model explains how melanocortin agonists cause weight loss Circuit model predicted that PYY 3-36 would inhibit appetite We know that leptin can no longer activate or inhibit neurons in a leptin resistant brain Can we design a therapy that works on the same neuronal pathways as leptin does?

19 Serotonin Serotonin 2C receptor is the target of Arena s obesity drug Lorcaserin. And is the subject of development by several other companies. Serotonin 1B receptor is not. 24

20 2002: PYY 3-36, a new satiety factor? Gut hormone, released post-prandially Predicted body weight effects based on Electrophysiology a screening tool Confirmed in mice (appetite suppressant + weight loss) Confirmed in humans (appetite suppressant) Scientific and popular media interest Unfortunately has narrow therapeutic index 25

21

22 Sonja Billes Eglantine Balland Weiyi Chen Pablo Enriori Aaron Eusterbrock Anne Evans Cecilia Garcia-Rudaz Erin Jobst Frank Koegler Tomris Mustafa Adnan Sali Stephanie Simonds Puspha Sinnayah Nick Wallingford Chun Xu Funding: Heart Foundation Monash University NH&MRC NIH: NIDDK, NCRR NovoNordisk Orexigen Therapeutics, Inc. Pfizer Australia VESKI Andrew Butler Russell Brown Wendy Brown Judy Cameron Iain Clarke Bill Colmers Roberto Coppari Sabrina Diano Ralph DiLeone Garron Dodd Joel Elmquist Sadaf Farooqi Jeff Friedman Frank Greenway U Gebhardt Bernadette Grayson Kevin Grove Lora Heisler Belinda Henry Tamas Horvath Julio Licinio Malcolm Low Brad Lowell Cathrine Laustrup Møller Dan Marks Charles Mobbs HL Müller Martin Myers Eduardo Nillni Geraldine Ooi Steve O Rahilly Eric Ravusin Thomas Reinehr Christian Roth David Spanswick Tony Tiganis Matthias Tschoep Ken Walder Matthew Watt Gareth Williams Sarah Williams Jørgen Wojtaszewski Birgitte Wulff