Life span, tissue triglyceride content and energy substrate utilization in wild-type and Atg/KO mice treated with the PPAR-α agonist Wy14643. (a,b) Treatment of 8-week-old Atg/KO mice on chow diet containing 0.1% WY14643 for 12 weeks prevented cardiac death (a) and lowered tissue triglyceride (TG) content (b), including in cardiac muscle and liver, compared to that observed in wild-type animals (n = 4). (c) Relative whole-body oxygen consumption of 8- to 9-week-old female wild-type and Atg/KO mice housed in metabolic cages (n = 5). (d) Respiratory quotients (calculated from the ratio of carbon dioxide elimination versus oxygen consumption) in Atg/KO mice compared to wild-type during the light period and in the fasted state indicating preferential glucose utilization as oxidative fuel (n = 5). Error bars show means ± s.d. *P < 0.05, **P < 0.01 and ***P < 0.001. (e) Scheme of the integration of Atgl-mediated lipolysis in PPAR signaling. Fatty acids from exogenous or endogenous sources are not available as ligands for nuclear receptor signaling but instead are activated to acyl-CoAs and subsequently oxidized or esterified to triglycerides. Atgl-mediated lipolysis of triglyceride stores preferentially generates ligands or precursors of ligands for nuclear receptors controlling mitochondrial function and OXPHOS. CD36, cluster of differentiation 36; Fatp, fatty acid transport protein; FFA, free fatty acid; TGRLP, triglyceride-rich lipoproteins.