Adipocyte Lipolysis is a Determinant of Skeletal Muscle Size During Fasting and Feeding

Intermittent fasting (IF) can lower fat mass, but also muscle mass. The mechanisms governing tissue partitioning during fasting remain unclear. During fasting, adipose-derived fatty acids from lipolysis and lipolysis-fueled hepatic ketogenesis maintain blood glucose and systemic energy homeostasis. We hypothesized that impaired lipolysis during fasting would shift substrate provision from adipose to muscle, increasing muscle catabolism during IF. We tested male adipocyte-specific adipose triglyceride lipase knockout (aKO) and littermate floxed-control mice during ad libitum feeding on a 10-week 5:2 IF protocol consisting of two non-consecutive 24-hour fasts and five ad libitum feeding days per week. After 10 weeks of IF, aKO mice had lower blood lipids and ketones and lost more lean mass and less fat mass than floxed-control mice when mice were fed a standard control diet and also retained more inguinal white adipose tissue and had lower hindlimb muscle mass when IF was compared to ad libitum feeding. Additionally, aKO mice had larger adipocytes, smaller muscle fibers, and increased expression of the atrogene, Atrogin1. We then provided exogenous lipids by feeding an obesogenic high fat diet (HFD). HFD-fed aKO mice had higher whole body fat oxidation and lower blood lipids and ketones than floxed-controls. Obese HFD-fed aKO mice still had smaller skeletal muscle myofibers and increased muscle atrogene expression despite smaller adipocytes during ad libitum feeding or IF. Therefore, adipocyte ATGL-mediated lipolysis is a determinant of skeletal muscle size, and lower lipolysis influences the balance of fat vs. muscle loss during fasting.