Obesity Treatments and Medical Research

Obesity and its associated diseases are now one of the main causes of morbidity and mortality worldwide. Despite the scale of this problem, successful preventative and treatment options for overweight and obesity remain limited. Dr Rachel Batterham at University College London has identified a protein which controls the brain’s perception of hunger and which could provide a therapy to control obesity and Type 2 Diabetes. Dr Batterham’s research has been part funded by Rosetrees Trust.^[1] Research to gain a greater understanding into the mechanisms that normally regulate body weight and how these processes are disturbed in obesity is essential to enable the development of effective therapies for obesity.

Insights from research into dieting and bariatric surgery

Dietary modifications, such as altering macronutrient composition and/or restricting caloric intake, are the first-line obesity treatments. However, dieting results in only moderate weight-loss and maintenance of weight-loss is often poor. In contrast, weight-loss surgery known as bariatric surgery is an efficacious treatment modality for obesity Gastric bypass surgery. Bariatric surgery results in durable weight loss and amelioration of obesity-associated co-morbidities, particularly type 2 diabetes mellitus, and reduced mortality.^[2] Moreover, following certain types of bariatric surgery, such as Roux-en Y gastric bypass, the metabolic benefits have been shown to occur independently of weight loss.^[3] Results from research studies undertaken to date suggest that compensatory alterations in circulating gut hormones may contribute to both the failure of dieting.^[4] In addition, new evidence that surgically induced alterations in circulating gut hormones help to mediate both the weight-loss and metabolic beneficial effects of bariatric surgery.^[4][5][6][7] Research aimed at understanding the mechanisms underlying the beneficial effects of bariatric surgery and altered gut hormone concentrations may lead to new non-surgical obesity treatments and therapies for type 2 diabetes.

Harnessing the gut to treat obesity

The gastrointestinal tract is the largest endocrine organ in the body producing hormones that have important sensing and signalling roles in regulating body weight and energy expenditure.^[8][9] A promising new area of obesity and diabetes research is focussed on targeting gut hormone systems.^[10]

Peptide YY

Peptide YY (PYY), a gut hormone that is mainly produced by the distal gut, has been shown to reduce appetite and food intake in normal weight and obese human subjects ^[11][12] Peptide YY . The physiological role of this hormone in regulating body weight has been confirmed by the finding that genetically modified mice that lack this hormone eat more and develop obesity and impaired glucose regulation.^[13] When these Pyy-lacking mice are given injections of PYY their obesity resolves. Research has shown that obese mice and humans have low circulating PYY concentrations.^[12][14] These findings suggest that PYY-deficiency might contribute to the pathogenesis of obesity.

PYY and the brain

Body weight is regulated primarily by the brain. Two homeostatic areas, the hypothalamus and brainstem key areas that govern primitive functions, play a major role in regulating appetite and studies in rodents have shown that PYY acts upon these brain areas. In today’s obesogenic environment food is abundant and rewarding. In addition, eating plays an important role in many social interactions and as a consequence people often when they are eat when they are not hungry. Ideally therapeutic strategies aimed at reducing body weight need to target both primitive brain regions that regulate hunger and also higher brain regions that control reward. To investigate in humans the brain circuits upon which PYY acts a double-blind placebo controlled study was undertaken combining intravenous PYY infusion with continuous functional magnetic resonance imaging and physiological and behavioural measures including assessment of subsequent food intake.^[15] These studies revealed that PYY acts upon the hypothalamus, brainstem and brain reward regions. These findings suggest that targeting the PYY system may offer an effective therapeutic strategy for the treatment of obesity.

References

1. ^ = "Rosetrees Trust". http://www.rosetreestrust.co.uk =. 
2. ^ Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H, Lystig T, Sullivan M, Bouchard C, Carlsson B, Bengtsson C, Dahlgren S, Gummesson A, Jacobson P, Karlsson J, Lindroos AK, Lonroth H, Naslund I, Olbers T, Stenlof K, Torgerson J, Agren G, Carlsson LM: Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 357:741-752, 2007. 
3. ^ Karra E, Yousseif A, Batterham RL: Mechanisms facilitating weight loss and resolution of type 2 diabetes following bariatric surgery. Trends Endocrinol Metab 21:337-344, 2010. 
4. ^ ^{a b} Chandarana K, Gelegen C, Karra E, Choudhury AI, Drew ME, Fauveau V, Viollet B, Andreelli F, Withers DJ, Batterham RL: Diet and gastrointestinal bypass-induced weight loss: the roles of ghrelin and peptide YY. Diabetes 60:810-818, 2011. 
5. ^ le Roux CW, Aylwin SJ, Batterham RL, Borg CM, Coyle F, Prasad V, Shurey S, Ghatei MA, Patel AG, Bloom SR: Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg 243:108-114, 2006. 
6. ^ Morinigo R, Vidal J, Lacy AM, Delgado S, Casamitjana R, Gomis R: Circulating peptide YY, weight loss, and glucose homeostasis after gastric bypass surgery in morbidly obese subjects. Ann Surg 247:270-275, 2008. 
7. ^ Cummings DE: Endocrine mechanisms mediating remission of diabetes after gastric bypass surgery. Int J Obes (Lond) 33 Suppl 1:S33-40, 2009. 
8. ^ Cummings DE, Overduin J: Gastrointestinal regulation of food intake. J Clin Invest 117:13-23, 2007. 
9. ^ Karra E, Batterham RL: The role of gut hormones in the regulation of body weight and energy homeostasis. Mol Cell Endocrinol 316:120-128, 2010. 
10. ^ = "Rosetrees Trust". http://www.rosetreestrust.co.uk/2011/05/obesity-research/ =. 
11. ^ Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD, Bloom SR: Gut hormone PYY3-36 physiologically inhibits food intake. 418:650-654, 2002. 
12. ^ ^{a b} Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR: Inhibition of Food Intake in Obese Subjects by Peptide YY3-36. N Engl J Med 349:941-948, 2003. 
13. ^ Batterham RL, Heffron H, Kapoor S, Chivers JE, Chandarana K, Herzog H, Le Roux CW, Thomas EL, Bell JD, Withers DJ: Critical role for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metabolism 4:223-233, 2006. 
14. ^ le Roux CW, Batterham RL, Aylwin SJB, Patterson M, Borg CM, Wynne KJ, Kent A, Vincent RP, Gardiner J, Ghatei MA, Bloom SR: Attenuated Peptide YY Release in Obese Subjects Is Associated with Reduced Satiety. Endocrinology 147:3-8, 2006. 
15. ^ Batterham RL, ffytche DH, Rosenthal JM, Zelaya FO, Barker GJ, Withers DJ, Williams SC: PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans. Nature 450:106-109, 2007.