A twin study of obesity pathogenesis using fMRI

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ABSTRACT The long-term health benefits of obesity treatment are limited by the weight regain that almost universally follows a weight loss intervention, frustrating patients and clinicians alike. In lay terms, a new, higher “set point” seems to occur after people gain weight, and research shows that processes of energy homeostasis, directed by neurons in the arcuate nucleus of the hypothalamus, vigorously defend the higher level of adiposity for years, promoting weight regain after behavioral weight loss. Bariatric surgery, however, results in weight loss that is more durable over time. These phenomena remain incompletely understood. The current proposal endeavors to address this crucial scientific gap by investigating the brain's role in the persistence of obesity and weight regain after weight loss. Specifically, studies in rodents show that diet-induced weight gain requires an inflammatory and cellular response, known as gliosis, within the arcuate nucleus of the hypothalamus and that this gliosis persists with continued dietary exposure. Importantly, gliosis is detectable in mice and humans by magnetic resonance imaging (MRI). Using MRI, the investigators discovered the first evidence of hypothalamic gliosis in obese humans. The investigators have also shown that hypothalamic gliosis is improved by Roux-en-Y gastric bypass (RYGB) surgery, suggesting that the efficacy and durability of weight loss via bariatric surgery could be partially explained by its ability to reverse gliosis. New findings show that hypothalamic gliosis negatively impacts brain regulation of appetite. Based on such findings, the proposed research investigates novel questions about the possible implications of hypothalamic gliosis for clinical weight management. First, it will determine whether the extent of hypothalamic gliosis present when people with obesity start a behavioral weight loss program is related to their success in treatment or weight regain after treatment. Second, the current proposal also addresses the question of whether gliosis is reduced to a greater extent when weight loss occurs by RYGB than by lifestyle change alone. Finally, this investigation uses a rodent study to test the role of 2 different hypothalamic glial cell types in weight regain after weight loss. In sum, basic science advances have identified hypothalamic cellular responses that facilitate weight gain during times of nutritional abundance, but this biological process is also capable of forming glial scars that are detrimental to neuronal functioning. The current research therefore investigates the implications of hypothalamic gliosis for humans undergoing obesity treatment. Achieving a better understanding of the role of the brain in successful obesity treatment could open new avenues for research, intervention, and prevention to alleviate the health risks of obesity.