Interaction between adipose tissue and central clock via the splanchnic nerve pathway for regulation of energy balance

Iowa City Va Medical Center, Iowa City IA

Investigators

Linked publications, trials & patents

Abstract

Obesity is a growing problem in the US, with veterans being at a higher risk of developing it along with diabetes and other obesity-related conditions. Bariatric surgery is one of the most common and effective invasive therapy offered to patients with severe obesity. Time-restricted feeding (TRF) behavior is one of the popular and wide-spread non-invasive therapies used to induce weight loss among patients and practitioners. Our research seeks to explore the role of the gut's "splanchnic neuron fibers" in communicating signals between the adipose tissue- “clock” and the brain- “clock” to activate thermogenesis in fat and determine how these therapies affect the molecular clock to induce their effect on energy homeostasis. Previous studies have shown that Roux-en-Y gastric bypass (RYGB) induces its metabolic effects by activating the splanchnic/ sympathetic nerve activity sub-serving the gut and mesentery to induce fat thermogenesis. Selective denervation of this tract leads to complete loss of all RYGB-induced metabolic effects. Similarly, TRF has been shown to induce an increase in efferent sympathetic splanchnic nerve activity compared to ad libitum feeding and it can rescue the abnormal metabolic derangements on energy expenditure in forebrain-specific bmal1 knock out mice. On the other hand, it was recently found that TRF could not rescue the loss of fat thermogenesis that was observed in adipose tissue-deficient clock. This data suggests that the molecular clock in adipose tissue and brain play a key role in energy homeostasis and communicate through afferent splanchnic neurons to activate efferent splanchnic neurons serving the mesentery and white adipose tissue to induce fat thermogenesis. The aim of this study is to explore the role of clock machinery in controlling energy homeostasis following TRF and RYGB and the requirement of the splanchnic nerve fibers in this regulation . Aim #1 will examine the capacity of peripheral clock within fat tissue to regulate afferent splanchnic nerve activity and its role in regulating energy balance during TRF and RYGB. Aim #2 will assess the ability of forebrain-specific clock machinery in regulating efferent splanchnic activity and subsequently fat thermogenesis in the setting of TRF and RYGB. Identifying the neuronal and neuro-molecular pathways used by both RYGB and TRF to induce their metabolic effects could lead to the development of novel treatments for obesity. By understanding how the molecular clock in the adipose tissue and brain regulates energy homeostasis in response to RYGB and TRF, it may be possible to develop more effective, and less invasive therapies for obesity.