Giovanni Fanni: Metabolic effects of obesity surgery: Role of the brain and neurohormonal pathways

Abstract

Obesity is a global health concern associated with increased morbidity and mortality, yet effective treatment strategies are lacking. So far, of all available treatments bariatric surgery has been shown to induce considerable and durable weight loss.

Recent evidence suggests that profound changes are happening in the brain and in the neuroendocrine system after gastric bypass, leading to the question “Is bariatric surgery brain surgery?”. Therefore, investigation into the meaning and significance of these changes is warranted to better depict the role of the brain in mediating the favorable metabolic adaptations induced by bariatric surgery.

This doctoral project aims to cast light on the brain- and hormone-mediated mechanisms that underlie the beneficial metabolic effects of bariatric surgery, and to pave the way to the development of new strategies for the prevention and treatment of obesity and T2D.

We deploy state-of-the-art methods combined, including the hyperinsulinemic glucose clamp, neuroimaging techniques, and hormonal measurements to translationally address the research question. Investigations are performed in the fasting state and under dynamic metabolic challenges, such as intravenous arginine challenge, oral glucose load, or hyperinsulinemic normo- and hypoglycemia, since metabolism is never fully understandable only in the fasting state.

In paper I, we show how gastric bypass alters brain connectivity of several neural pathways involved in reward, inhibitory control, and energy homeostasis during hypoglycemia. In paper II, we explored how gastric bypass is associated with region-specific patterns of changes in glucose uptake in the brain. Paper III shows changes in ACTH, cortisol, GH, and gut hormone levels during the OGTT after gastric bypass in individuals with type 2 diabetes. In paper IV, we report changes in the activity of several hormonal systems during an oral glucose load occurring shortly after bariatric surgery but not after a low-energy diet despite similar weight loss.

Altogether, these results expand the knowledge about the mechanisms underlying the beneficial metabolic effects of bariatric surgery, highlighting the importance of exploring further the role of the brain and neuroendocrine systems, eventually to identify new therapeutic targets against obesity and T2D.