Loss of Sirt6 in adipocytes impairs the ability of adipose tissue to adapt to intermittent fasting

Abstract

Intermittent fasting (IF) is gaining popularity for its effectiveness in improving overall health, including its effectiveness in achieving weight loss and euglycemia. The molecular mechanisms of IF, however, are not well understood. This study investigated the relationship between adipocyte sirtuin 6 (Sirt6) and the metabolic benefits of IF. Adipocyte-specific Sirt6-knockout (aS6KO) mice and wild-type littermates were fed a high-fat diet (HFD) ad libitum for four weeks and then subjected to 12 weeks on a 2:1 IF regimen consisting of two days of feeding followed by one day of fasting. Compared with wild-type mice, aS6KO mice subjected to HFD + IF exhibited a diminished response, as reflected by their glucose and insulin intolerance, reduced energy expenditure and adipose tissue browning, and increased inflammation of white adipose tissue. Sirt6 deficiency in hepatocytes or in myeloid cells did not impair adaptation to IF. Finally, the results indicated that the impaired adipose tissue browning and reduced expression of UCP1 in aS6KO mice were accompanied by downregulation of p38 MAPK/ATF2 signaling. Our findings indicate that Sirt6 in adipocytes is critical to obtaining the improved glucose metabolism and metabolic profiles conferred by IF and that maintaining high levels of Sirt6 in adipocytes may mimic the health benefits of IF. Fat metabolism: facilitating responses to intermittent fasting The health benefits of intermittent fasting regimens are mediated in part by a protein 'switch' that modulates metabolic and inflammatory activity in fatty tissue. Several studies have linked such dietary regimens, which entail alternating periods of fasting and eating, to improved metabolic health. Researchers led by Byung-Hyun Park and Eun Ju Bae at Chonbuk National University, Jeonju, South Korea, have now demonstrated that the sirtuin 6 protein coordinates important physiological changes in response to such diets. The researchers noted that intermittent fasting mitigated the effects of a high-fat diet in control mice. In contrast, mice lacking sirtuin 6 in their fat cells exhibited features of metabolic syndrome under these conditions, including active inflammation in fatty tissue and reduced response to insulin. These results suggest that therapies that modulate sirtuin 6 could mirror the benefits achieved through intermittent fasting.