July 18, 2023

Time-restricted feeding promotes muscle function through purine cycle and AMPK signaling in Drosophila obesity models

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Girish Melkani, Ph.D.Girish Melkani, Ph.D.Girish Melkani, Ph.D., associate professor in the Department of Pathology, is the latest winner of the UAB Heersink School of Medicine's Featured Discovery. This initiative celebrates important research from Heersink faculty members.

Melkani’s lab study, titled "Time-restricted feeding promotes muscle function through purine cycle and AMPK signaling in Drosophila obesity models,” was recently published in Nature Communications. Two graduate students in Melkani’s lab, Chris Livelo and Yiming Guo, are co-first authors of the paper.

“Obesity is a global health concern associated with various health issues and economic challenges,” said Melkani, researcher in the Division of Molecular and Cellular Pathology. “It is often accompanied by comorbidities such as cardiovascular disease (CVD), dementia, and compromised skeletal muscle function. The major contributors to obesity are caloric-rich diets and genetic predisposition.”

The study implemented time-restricted feeding (TRF) as a dietary intervention to tackle obesity-related skeletal muscle problems and metabolic impairments. The results indicate that TRF has the potential to modulate pathways that alleviate obesity and offer new targets for therapeutic approaches. Moreover, implementing time-restricted eating (TRE) as a non-pharmacological intervention could significantly reduce obesity-related comorbidities and health disparities, particularly in the Deep South.

“Using diet and genetically obese Drosophila (fruit fly) models, we uncovered that TRF potentially regulates common and distinct novel pathways to attenuate obesity,” said Melkani. “The findings from this study may help researchers develop effective treatments by providing new targets for patients affected by obesity.”

The Heersink communications staff sat with Dr. Melkani to gain insight into the study, UAB, and the science community.

Q: What compelled you to pursue this research?

My research group investigated the effects of a behavior intervention called "TRF/TRE" where food access is limited to less than 12 hours during the active period. This intervention reduces aging, obesity, and metabolic disorders, but its mechanisms are not fully understood. Using Drosophila models and genetic tools, we studied TRF's effects on diet and genetic obesity models. We discovered that TRF improves muscle function by modulating pathways specific to different obesogenic challenges. The model mimics human patient phenotypes and suggests potential obesity treatment targets. We, as researchers, are fascinated by the significant benefits achieved through simple adjustments to daily feeding windows.

Q: What was your most unexpected finding?

We found it exciting and unexpected that TRF can confer beneficial effects through potentially unique pathways in different obesity models (diet and genetically induced) rather than just a common pathway for all types of obesity. This suggests the need for a more personalized approach to therapy in addressing obesity caused by different independent factors.

Q: How do you feel your research will impact the science community?

The obesity epidemic has led to increased rates of CVD, diabetes, and other metabolic disorders. To address the comorbidities associated with obesity, it is crucial to investigate the interplay between genes and the environment. Our research aims to bridge the gap in understanding these risks and explore potential lifestyle interventions using a genetic model system. Through our innovative and cost-effective non-pharmacological approach, combined with unbiased transcriptome analysis, we have identified candidate genes and pathways that play a role in the beneficial effects of TRF (time-restricted feeding). Our findings can significantly contribute to scientists studying TRF in obesity and offer a fresh perspective that TRF may exert its benefits through different mechanisms depending on the underlying causes of obesity.

Q: What is your research’s relevance to human disease?

Understanding the mechanisms behind TRF can aid future research in developing effective therapies for obesity and its associated comorbidities. Our study identified distinct lipidomic patterns in patient plasma associated with race, CVD, and obesity, addressing health disparities and prevalent comorbidities in the Deep South. [Lipodomics study the structure and function of the complete lipids (the lipidome) produced in a given cell or organism and their interactions with other lipids, proteins, and metabolites.] Genetic validation of these lipidomic patterns will enhance our understanding of factors contributing to obesity-related comorbidities. TRF interventions can be implemented through community-based approaches, particularly in the Deep South, to improve cardiovascular health and other outcomes linked to preventing or slowing obesity-related comorbidities.

Q: What do you find makes the science community here unique?

UAB's multidisciplinary scientific community supports and facilitates my lab projects in various areas, such as circadian, cardiac, neurological, metabolic, and aging research. My research group uses clinically relevant genetic models like Drosophila to understand the underlying causes of circadian and metabolic disorders associated with CVD, myofibrillar-myopathies, neuropathies, sleep/insomnia, and aging. We employ a combination of physiological, cellular-molecular, genetic, genomic, and nutritional approaches to investigate how lifestyle factors (including circadian rhythms and TRF) and genetic factors contribute to maintaining cellular, tissue, and organ integrity, influencing overall organismal physiology. Collaboration and feedback from researchers across basic, translational, and clinical fields enrich our diverse projects. Affiliated with multiple research centers provides unique opportunities to pursue comprehensive and multidisciplinary approaches, addressing our genetic models' pathophysiological basis and clinical relevance.