Researchers investigating the reasons why muscular function declines as a result of obesity used obese fruit flies as their experimental subjects. Skeletal muscle in humans is essential to metabolism, and muscle dysfunction brought on by obesity can result in insulin resistance and low energy.
It’s interesting to note that research using a variety of animal models has demonstrated that time-restricted feeding is a natural, non-pharmaceutical strategy that guards against fat, aging, and circadian disturbance in peripheral tissues like skeletal muscle. The mechanics underpinning those advantages weren’t understood, though.
Obese Drosophila, also known as Drosophila melanogaster in scientific terms, have shown improved muscle performance, decreased intramuscular fat, lowered levels of phospho-AKT, and a decrease in the marker of insulin resistance when subjected to obesogenic challenges and treated with time-restricted feeding. Intramyocellular lipids and triglycerides deposited within skeletal muscle cells can be harmful if not routinely depleted.
The current study, led by University of Alabama at Birmingham researcher Girish Melkani, Ph.D., provides a potential mechanistic basis for the benefits mediated by time-restricted feeding.
In all time-restricted feeding situations, Melkani and colleagues discovered that glycine production and utilization-related genes were upregulated, whereas a crucial enzyme involved in triglyceride synthesis was downregulated.
Obesity is associated with various comorbidities, especially high-caloric diets and genetic predisposition. This study elucidates potential mechanisms behind time-restricted feeding’s protective properties against skeletal muscle dysfunction and metabolic impairment induced by obesity.
Girish Melkani
Additionally, time-restricted feeding induced upregulation in genes and increases in metabolites related to the purine cycle in the high-fat diet fruit fly model of obesity, and it led to upregulation of genes and increases in metabolites relating to glycolysis, glycogen metabolism, the tricarboxylic acid cycle and the electron transport chain connected by AMP kinase signaling, in a genetic fruit fly model of obesity mutated in sphingosine kinase, or Sk2.
“The prevalence of obesity continues to be a worldwide growing issue associated with crippling health care and economic burdens,” said Melkani, an associate professor in the UAB Department of Pathology Division of Molecular and Cellular Pathology. “Obesity is associated with various comorbidities, especially high-caloric diets and genetic predisposition. This study elucidates potential mechanisms behind time-restricted feeding’s protective properties against skeletal muscle dysfunction and metabolic impairment induced by obesity.”
“The findings may pave the way for future time-restricted feeding studies in muscle, providing a natural and affordable form of alternative therapy for managing pathologies related to metabolism and obesity,” Melkani says.
Melkani also described his long-term research goals. “Recent genome-wide association studies and exon sequencing approaches have identified a linkage of additional genes with genetic obesity. Obesity is strongly linked with cardiovascular disease and dementia. However, the mechanistic linkage remains poorly understood, and urgent interventions are required to mitigate these disorders.”
“Our mechanistic approach along with interventions including time-restricted eating will be highly useful in addressing and treating the obesity, cardiovascular disease and dementia disparities seen in the Deep South.”
The fruit fly is an amenable model for studying human metabolic diseases. The fruit flies used in the current study’s high-fat diet model of obesity are given a diet that is enhanced with 5 percent coconut oil, and they are free to eat whenever they choose.
Only 12 hours a day are available for the time-restricted feeding, high-fat diet fruit flies. The Sk2 fly model of obesity has a mutation in the Sk2 gene that causes a ceramide accumulation that is a hallmark of the condition.
Ten to twenty fruit flies were released into a Plexiglas box as part of the current study’s experimental methodology, and the ability of each fly to fly up, horizontally, downward, or not at all was measured for each fly. Techniques also included measuring the amounts of glycine, ATP, and metabolites, as well as performing cytological tests on muscle tissue and abdominal fat bodies.
Co-first authors of the study, “Time-restricted feeding promotes muscle function through purine cycle and AMPK signaling in Drosophila obesity models,” are Christopher Livelo and Yiming Guo, graduate students in the UAB Department of Pathology.
Co-authors with Melkani, Livelo and Guo are Farah Abou Daya and Vasanthi Rajasekaran, UAB Department of Pathology; Shweta Varshney, Hiep D. Le and Satchidananda Panda, Salk Institute for Biological Studies, La Jolla, California; and Stephen Barnes, UAB Department of Pharmacology and Toxicology.
Support came from National Institutes of Health grants AG065992 and AG068550, UAB Startup Funds 3123226 and 3123227, and grants from the Wu-Tsai Human Performance Alliance and the Wu-Tsai Foundation.
