Accumbal adaptations that contribute to weight regain after weight loss

Project Summary/Abstract Losing weight can be life saving for people with obesity. However, among patients that do lose significant weight, most have trouble keeping the weight off. People with obesity that lose weight experience physiological, neural, and behavioral changes that drive weight regain. These changes resemble adaptive mechanisms that defend body weight during periods of food scarcity, but for people trying to achieve a healthy body weight and stay there, these mechanisms are decidedly maladaptive. Intervening to counteract them has the potential to revolutionize the clinical approach to weight loss for people with obesity. The objective of this proposal is to understand how the function of a brain area known as the nucleus accumbens is altered across the weight “gain-loss-regain” cycle in mice. Our central hypothesis is that obesity is associated with adaptations in the brain’s reward circuitry that enhance the pursuit of palatable foods, promoting weight regain after obese animals lose weight, and thereby perpetuating this cycle. In Aim 1, we will use ex vivo electrophysiological approaches to monitor changes in intrinsic and synaptic properties of accumbal neurons as obese mice lose weight, critically determining adaptations that persist after weight loss. In Aim 2, we will employ in vivo calcium imaging to measure the activity of specific populations of accumbal neurons as mice gain, lose, and regain weight. Finally, in Aim 3 we will use viral genetic strategies to selectively silence specific populations of accumbal neurons to determine whether this: 1) facilitates weight loss in obese mice that remain on a high-fat diet; and/or 2) inhibits weight re-gain in formerly obese mice who have lost weight. Our long-term goal is to understand how obesity alters reward circuitry and discover methods for reversing these changes. This research will provide a critical foundation to advance efforts to improve weight loss outcomes in people with obesity.