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

Dandan Wu,Byung-Hyun Park,Eun Ju Bae,In Hyuk Bang

doi:10.1038/s12276-021-00664-1

Dandan Wu, Byung-Hyun Park + Show 2 more

Open Access

https://doi.org/10.1038/s12276-021-00664-1

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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.

Highlights

Obesity, which increases the risk of developing metabolic diseases such as type 2 diabetes, is a global epidemic
MATERIALS AND METHODS Animals and diet regimens Eight-week-old male C57BL/6 mice were subdivided into three groups: the first and second groups were fed a normal chow diet (NCD) or high-fat diet (HFD) ad libitum over a 16-week period of study, while the third group was fed a HFD for the first four weeks and switched to an Intermittent fasting (IF) regimen consisting of two-day feeding/one-day fasting periods (2:1 IF) for the remaining 12 weeks (Supplementary Fig. 1a). Adipocyte-specific Sirt6-knockout (aS6KO) mice (Sirt6flox/flox;Adipoq-Cre) were generated by crossing Sirt6flox/flox mice (B6;129-Sirt6tm1Ygu/J) and Adipoq-Cre mice (B6.FVB-Tg(Adipoq-cre)1Evdr/J) as previously described[30]
IF increases the expression of Sirt[6] in the adipose tissue (AT) of HFD-fed mice In this study, we applied an isocaloric IF regimen to exclude the possibility of weight loss due to reduced caloric intake[33]

Summary

Introduction

Obesity, which increases the risk of developing metabolic diseases such as type 2 diabetes, is a global epidemic. Physical activity and dietary manipulation are the effective means of achieving weight loss and treating obesity-related diseases. Calorie restriction (CR) has long been known to cause weight loss and extend the health span of animals[1,2]. Intermittent fasting (IF), known as intermittent energy restriction, is an eating pattern that cycles between periods of fasting and eating and is gaining popularity as an alternative to CR for its effectiveness in improving overall health[3,4]. The most common IF regimens in humans include alternate-day fasting, twice-weekly fasting, and time-restricted feeding[3]. IF has been shown to promote health and reduce the risk of many chronic diseases, including metabolic syndrome, as well as various cancers, cardiovascular maladies, and neurodegenerative diseases[4,8,9]

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