Insulin and IRF4 Suppress Fat Loss and Promote Muscle Loss During Intermittent Fasting in Obesity

Abstract

Obesity has become a worldwide epidemic fuelled by overnutrition. IF alters feeding windows and can lower body mass. It is not clear why only some people lose weight and why there are varying degrees of fat loss versus muscle loss during IF. Lipolysis liberates stored fat, mainly from adipose tissue during fasting. Insulin inhibits lipolysis, but it was unknown if elevated insulin or blocking aspects of lipolysis alters fat loss versus muscle loss during IF. This is important because obesity is associated with elevated blood insulin. Here, we showed that causing chronic high insulin by implanting a slow-release insulin pellet, deletion of adipocyte interferon regulatory factor 4 (IRF4), or deletion of adipose tissue triglyceride lipase (ATGL) all blunt lipolysis in mice. We then tested these factors in mouse models of diet-induced obesity and IF. Mice were placed on a 45% kcal from fat diet and either left to consume food ad-libitum (AL) or put on a 5:2 IF protocol for 10 weeks, which consisted of two 24-hour fast periods on non-consecutive days of the week. Following 10 weeks of 5:2 IF and high fat diet (HFD) feeding, all mice that engaged in IF lost significantly more body mass than their AL counterparts. However, mice that had high insulin, or Irf4 deletion lost less white adipose tissue (WAT) and more muscle, indicated by smaller hindlimb tibialis anterior (TA) muscles. Deletion of Atgl in adipocytes did not alter the muscle fat balance in HFD-fed mice during IF. Humans with obesity and high insulin also lost more lean mass after an acute 48hr fast compared to lean controls. Therefore, insulin status and regulation of adipocyte IRF4 may be important factors to consider before prescribing IF for weight loss as lower muscle mass can be detrimental to metabolic and overall health status.