Rhythmic feeding pattern preserves fruit fly muscle function under conditions of obesity

Obese flies are the experimental subjects in a Nature communications study of the causes of the decrease in muscle function due to obesity. In humans, skeletal muscle plays a critical role in metabolism, and muscle dysfunction due to human obesity can lead to insulin resistance and reduced energy levels.

Interestingly, studies in various animal models have shown that time-restricted feeding—a natural non-pharmacological intervention—protects against obesity, aging, and circadian disruption in peripheral tissues such as skeletal muscle. However, the mechanisms underlying these benefits were not known.

In fruit flies—scientifically known as Drosophila melanogaster—obese Drosophila subjected to obesity challenges and treated with time-restricted feeding have shown improved muscle performance, reduced intramuscular fat, reduced levels of phospho-AKT and a reduction in insulin resistance. Intramyocellular lipids and triglycerides deposited in skeletal muscle cells can be harmful if not regularly depleted.

The current study, led by University of Alabama at Birmingham researcher Girish Melkani, Ph.D., provides a possible mechanistic basis for the benefits mediated by time-restricted feeding. Melkani and colleagues found that time-restricted feeding caused upregulation of genes related to glycine production and utilization and downregulation of a key enzyme involved in triglyceride synthesis, across all time-restricted feeding conditions.

In addition, time-restricted feeding induced upregulation of genes and increases in metabolites related to the purine cycle in the high-fat diet model of obesity, and led to upregulation of genes and increases in metabolites related to glycolysis, glycogen metabolism. tricarboxylic acid cycle and the electron transport chain linked to AMP kinase signaling in a sphingosine kinase or Sk2 mutant genetic fly model of obesity.

“The prevalence of obesity continues to be an internationally growing issue associated with crippling health care and economic burdens,” said Melkani, an associate professor in the UAB Department of Molecular and Cellular Pathology. “Obesity is associated with various comorbidities, especially with high-calorie diets and genetic predisposition. This study elucidates potential mechanisms behind the protective properties of time-restricted feeding against obesity-induced skeletal muscle dysfunction and metabolic damage.” .”

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 metabolic and obesity-related pathologies, Melkani says.

Melkani also outlined his long-term research goals. “Recent genome-wide association studies and exon sequencing approaches have identified an association of additional genes with genetic obesity. Obesity is strongly associated with cardiovascular disease and dementia. However, the mechanistic link remains poorly understood and urgent interventions are needed to mitigate these disorders.

“Our mechanistic approach—along with interventions including time-restricted feeding—will be very useful in addressing and treating disparities in obesity, cardiovascular disease, and dementia seen in the Deep South.”

The fly is an amenable model for the study of human metabolic diseases. In the current study, the high-fat diet obesity model has a diet supplemented with 5 percent coconut oil, and fruit flies are allowed to feed 24 hours a day. High-feeding flies with limited feeding time only have access to the high-fat diet 12 hours per day. The Sk2 fly model of obesity has a mutation in the Sk2 gene, leading to an accumulation of ceramide, which is implicated as an obesity factor.

Experimental methods for muscle performance in the current study included flight tests where 10 to 20 fruit flies are released into a Plexiglas box and each fly’s ability to fly up, horizontally, down, or not is measured. Methods also included cytological analysis of muscle tissue and abdominal fat, gene expression analyses, and measurement of glycine, ATP, and metabolite levels.