Time-restricted feeding restores muscle function in Drosophila models of obesity and circadian-rhythm disruption

Abstract

Pathological obesity can result from genetic predisposition, obesogenic diet, and circadian rhythm disruption. Obesity compromises function of muscle, which accounts for a majority of body mass. Behavioral intervention that can counteract obesity arising from genetic, diet or circadian disruption and can improve muscle function holds untapped potential to combat the obesity epidemic. Here we show that Drosophila melanogaster (fruit fly) subject to obesogenic challenges exhibits metabolic disease phenotypes in skeletal muscle; sarcomere disorganization, mitochondrial deformation, upregulation of Phospho-AKT level, aberrant intramuscular lipid infiltration, and insulin resistance. Imposing time-restricted feeding (TRF) paradigm in which flies were fed for 12 h during the day counteracts obesity-induced dysmetabolism and improves muscle performance by suppressing intramuscular fat deposits, Phospho-AKT level, mitochondrial aberrations, and markers of insulin resistance. Importantly, TRF was effective even in an irregular lighting schedule mimicking shiftwork. Hence, TRF is an effective dietary intervention for combating metabolic dysfunction arising from multiple causes.

Time-restricted feeding prolongs lifespan inDrosophilain a peripheral clock-dependent manner

“…This deviation from the classic "S-shaped" survival plot seems to be a feature of virgin Drosophila, as previous studies also reported similar survival dynamics (Markow, 2011;Villanueva et al, 2019). In flies, TRF has been shown to have beneficial effects on sleep in males ( (Gill et al, 2015), female data not shown in that study), and improve cardiac health and muscle function in both sexes (Gill et al, 2015;Villanueva et al, 2019). Previous work examining the effect of TRF on longevity in both sexes found no benefit, in contrast to the data presented here.…”

“…In addition to DR including caloric restriction and restricting uptake of certain nutrients or amino acids, other dietary interventions have been shown to have positive effects on aging: intermittent fasting, which includes various protocols of feeding or eating and fasting for longer than 24h (Patterson and Sears, 2017), and time-restricted feeding (TRF), where food intake is restricted daily to certain hours of the day (Chaix et al, 2019b). In Drosophila, TRF has been shown to attenuate age-related cardiac decline during aging (Gill et al, 2015), as well as increase sleep and muscle function (Villanueva et al, 2019). In mice, TRF lowers blood cholesterol and sugar levels, reduces body weight, inflammation and dysbiosis, while increasing energy expenditure, motor control and endurance (Chaix et al, 2019b).…”

Circadian rhythms and obesity: Timekeeping governs lipid metabolism

“…30 However, various studies show that circadian disruption, either genetic or environmental variants (ie, nocturnal light exposure, sleep disorders, social jet lag, and late-night snacking), widely affects host lipid metabolism and accelerates the development of obesity. [31][32][33][34] For example, both Clock mutant (delta 19) and Bmal1 knockout (KO) mice exhibit glucose intolerance, reduced insulin secretion, increased sensitivity to high-fat diet feeding, are hyperphagic and became overweight. [35][36][37] Additionally, glucose metabolism and systemic glucose homeostasis are also impaired in peripheral tissues-specific (skeletal muscle, beta cells and liver) Bmal1 KO models.…”

Mechanisms of Lifespan Regulation by Calorie Restriction and Intermittent Fasting in Model Organisms

“…However, a 3 h or 6 h starvation during the day was not enough to extend the lifespan [65]. Additionally, TRF did not increase the median lifespan of fruit flies, although TRF improved the muscle performance and attenuated age-related cardiac dysfunction [31,68].…”

“…A relatively diverse fasting study design can be carried out in fruit flies. In the case of ADF, food is provided every two days and fasting is performed for 24 h. Recent studies have found that a 2-day fed:5-day fasted IF regime [67] and a TRF regime with daily access to food during the day and water access during the night [68] can be implemented in fruit flies. In the IF regime's case, flies were treated for IF for the first 30 days of adulthood and then switched to an ad libitum diet due to high mortality by fasting in older flies [67].…”