Thursday, April 18, 2024
4/18/2024
Project Summary This project seeks to understand the metabolic mechanisms that drive high weight loss (WL) recidivism rates in individuals who successfully lose excess body weight (BW). WL triggers adaptations that lower metabolic rate at rest and during exercise, increasing susceptibility to weight regain (WR) and relapsed obesity. The underlying mechanisms remain unclear. Here, we propose to examine how the processes of WL and WR impact energy efficiency in heart and skeletal muscle (SkM), two major contributors to total body energy expenditure. In these tissues, up to 90% of ATP production is attributable to mitochondrial respiration; thus, changes in respiratory efficiency may directly impact whole-body metabolic rate. Previous work by our laboratory and others supports the notion that muscle mitochondrial efficiency is influenced both by the availability of, and capacity to oxidize circulating ketone bodies, byproducts of hepatic fat oxidation that serve as alternative fuels during periods of energy and/or carbohydrate restriction. The predominant ketone body, ß-hydroxybutyrate (BHB), is oxidized by mitochondrial ¿-hydroxybutyrate dehydrogenase 1 (BDH1). In both rodents and humans, enhanced BDH1 flux appears to confer cardioprotection in the context of heart failure. Additionally, our preliminary data show that BDH1 flux plays an essential role in mediating the health benefits of time-restricted feeding (TRF), a model of caloric restriction. Our findings further suggest that BDH1 mediates these outcomes by increasing mitochondrial efficiency via multiple mechanisms. While enhanced efficiency is viewed favorably under circumstances of chronic energetic stress, it might counteract WL and promote WR in response to anti-obesity interventions. Importantly, the contributions of muscle bioenergetics and/or BDH1 flux to WL recidivism have not been explored. To address this gap, we propose two specific aims to test our hypotheses that: 1) WL promotes mitochondrial remodeling and increases respiratory efficiency in heart and SKM, and 2) ketone catabolism through BDH1 is a key factor driving the adapted physiology of the weight-reduced state. The studies will employ a novel knockout (KO) mouse model lacking BDH1 specifically in heart and SkM. C57BL6/NJ control mice and BDH1 KO littermates will be exposed to a weight gain (WG)/WL/WR paradigm to examine both whole-body and mitochondrial physiology during weight cycling. Deep and comprehensive phenotyping of mitochondrial bioenergetics will be accomplished using a highly sophisticated respiratory diagnostics platform developed by our laboratory. Assessments of mitochondrial performance will then be combined with state-of-the-art, mass spectrometry-based metabolomics and proteomics to evaluate the impact of WL and/or BDH1 flux on mitochondrial remodeling. These studies will improve our understanding of the mechanisms that thwart WL maintenance and lead to relapsed obesity.
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