Regulation of Substrate Metabolism and Renin-Angiotensin System with Dietary and Pharmacological Interventions: Implications for Obesity and Related Disorders

This dissertation investigates the effects of the ketogenic diet (KD) on adipose tissue (AT) metabolism and renin-angiotensin system (RAS) function and potential implications for other tissues, including lung, heart and skeletal muscle. In the first study, it was demonstrated that despite increasing fat mass, a KD enhanced energy-dissipating mechanisms in white AT (WAT) and brown AT (BAT) by upregulating the machinery for triacylglycerol recycling in white adipocytes and uncoupled fatty acid (FA) oxidation and UCP1 protein levels in the BAT. These effects could potentially be attributed to the shift to the counterregulatory RAS arm in WAT observed in study 2, which has been shown to produce beneficial metabolic effects. In study 3, the effect of the KD on RAS components was investigated in the context of the lung and heart, where an obesity-induced elevation in pulmonary inflammation could underlie an increase in angiotensin converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 cellular infection. We observed that the obesogenic, high-fat sucrose-enriched (HFS) diet elevated the pulmonary content of this receptor, whereas the KD did not alter ACE2 levels. Moreover, the KD significantly suppressed inflammation, relative to the HFS group, in the lung. Because AT releases energy substrate for utilization in peripheral tissues, the KD also affects substrate preference and metabolism in skeletal muscle. To our knowledge, little has been done with respect the metabolic effects of a KD on muscles with distinct fiber-type compositions. Therefore, we assessed the effects of the KD on glucose, fat, and ketone metabolism in skeletal muscles. We observed that the KD increased fat oxidation and ketolytic capacity, when compared to the HFS group, in a fiber-type specific manner. However, irrespective of oxidative capacity, the KD preserved insulin-stimulated glucose metabolism, whereas the HFS diet suppressed this parameter. In our final study, we used a pharmacological intervention (the adiponectin mimetic ALY688) to alter AT glucose and fat metabolism. Despite not altering glucose uptake in Epid or Sc Ing adipocytes, ALY688 significantly enhanced glucose oxidation. Together, these projects explore dietary and pharmacological interventions that alter the metabolic and endocrine roles of AT and investigate non-adipose tissues under KD conditions.