Physiological changes underlying the weight loss plateau in humans

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Behavioral strategies for obesity treatment reliably result in weight loss and health benefits. However, weight loss typically plateaus at ~7–10% of total body weight (a plateau phase) after which weight regain is common, limiting the ability of most intervention strategies to modify obesity-related disease risk in a sustained manner. Overcoming these limitations requires advancing understanding of metabolic, appetitive, and neurological factors that counteract—and eventually halt—weight loss. Existing literature shows that weight loss evokes appetitive adaptations that include increased hunger and decreased satiety. The investigative team’s preliminary data add evidence that an impaired satiety response in brain regions controlling reward and motivation follows weight loss. Documented metabolic responses to weight loss include declines in total body and resting energy expenditure as well as increased metabolic efficiency in muscle and adipose tissue. We now present preliminary data using novel measures of mitochondrial metabolism indicating that a weight loss plateau is characterized by reductions in mitochondrial metabolic capacity in peripheral blood mononuclear cells. The proposed research aims to 1) test if an involuntary weight loss plateau is distinguished from other phases of weight loss by alterations in cellular bioenergetics across multiple tissue types including circulating blood cells, muscle, and adipose tissue; 2) test for neurophysiologic changes consistent with reduced satiety at an involuntary weight loss plateau and assess their relation to changes in metabolism; and 3) investigate predictors of a weight loss plateau using data collected at baseline and in real time during behavioral weight loss. To address these three Specific Aims, the multidisciplinary study team proposes a basic experimental study in humans using a remotely delivered group behavioral weight loss intervention to evoke and study plateau physiology. Real-time remote monitoring of weight loss trajectories will be used to individualize assessments for 130 adults with overweight or obesity to occur at baseline, during active weight loss, and at a weight loss plateau. Intensive phenotyping will include serial behavioral assessments and tasks, fasting and postprandial blood sampling, functional and structural brain magnetic resonance imaging, indirect calorimetry, and adipose and muscle biopsies to investigate the contribution of mitochondrial function and other pathways to this weight loss plateau. Future work will probe underlying mechanisms that trigger plateau physiology in a tissue-specific manner, using identified predictors to target individuals and timepoints. In sum, the proposed research uses an innovative, individualized approach to improve understanding of the physiological factors that make additional weight loss difficult once a weight loss plateau is reached. The long-term goal is to develop new approaches for extending weight loss and improving weight maintenance.