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. 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.
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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. 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. Results from research studies undertaken to date suggest that compensatory alterations in circulating gut hormones may contribute to both the failure of dieting. 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. 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. A promising new area of obesity and diabetes research is focussed on targeting gut hormone systems.
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 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. 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. 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 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. 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.