All ETDs from UAB

Advisory Committee Chair

Girish C Melkani

Advisory Committee Members

Eason B Hildreth

Rajasekaran N Soorappan

Courtney M Peterson

Document Type

Dissertation

Date of Award

2023

Abstract

Obesity is a global epidemic that affects countless numbers of people caused by genetic and environmental factors including circadian disruption, which poses significant health risks to skeletal muscle physiology and other tissues. While a feeding fasting intervention known as time-restricted feeding (TRF) has been shown to mitigate obesity-related muscle dysfunction, the underlying mechanisms remain a subject of investigation. In this study, we delve into potential mechanisms underlying TRF's protective effects on muscle physiology in the context of diet- and genetic-induced obesity using Drosophila models. Our findings reveal that TRF triggers the upregulation of key genes involved in glycine production (Sardh and CG5955) and utilization (Gnmt). Muscle-specific knockdown of Gnmt, Sardh, and CG5955 resulted in muscle dysfunction, ectopic lipid accumulation, and the loss of TRF-mediated benefits. Furthermore, our investigations unveiled distinct pathways affected by TRF under different obesogenic challenges. While TRF was found to enhance the purine cycle in diet-induced obesity (HFD), TRF activated AMPK and downstream signaling predominantly in genetic-induced obesity. Additionally the microbiome, which is sensitive to lifestyle changes like diet and obesity, can also play a role in muscle physiology. We explored TRF’s modulation of the microbiome and the consequences of microbiota removal on skeletal muscle physiology in wildtype and obese Drosophila models, highlighting the intricate interplay between diet, microbiota, and muscle physiology. Notably, (axenic) wildtype Drosophila exhibited reduced muscle performance, elevated insulin resistance and glucose levels, ectopic lipid accumulation, and decreased ATP levels compared to their conventional counterpart. Interestingly, in Drosophila obesity models, improved muscle performance, lower glucose levels, and increased ATP levels in axenic conditions was observed. TRF showed changes in the abundances of specific bacterial species, Acetobacter Pasteurianus and Staphylococcus Aureus, which, when supplemented, led to improvement/worsening (respectively) of skeletal muscle physiology. In summary, our study investigates the pleiotropic impacts of TRF benefits on muscle physiology under varying obesogenic challenges. We investigate the intricate relationship between TRF and the microbiome, pathway modulation, and its impacts on skeletal muscle physiology. These findings provide insights into potential targets for obesity treatment and furthers our understanding in regards to TRF modulated attenuation of obese associated phenotypes in muscle.

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