Sirtuin 1 (SIRT1), an NAD+-dependent protein deacetylase, regulates a host of target proteins, including peroxisome proliferator–activated receptor (PPAR)-γ coactivator-1α (PGC-1α), a transcriptional coregulator that binds to numerous transcription factors in response to deacetylation to promote mitochondrial biogenesis and oxidative metabolism. Our laboratory and others have shown that adipose triglyceride lipase (ATGL) increases the activity of the nuclear receptor PPAR-α, a PGC-1α binding partner, to promote fatty acid oxidation. Fatty acids bind and activate PPAR-α; therefore, it has been presumed that fatty acids derived from ATGL-catalyzed lipolysis act as PPAR-α ligands. We provide an alternate mechanism that links ATGL to PPAR-α signaling. We show that SIRT1 deacetylase activity is positively regulated by ATGL to promote PGC-1α signaling. In addition, ATGL mediates the effects of β-adrenergic signaling on SIRT1 activity, and PGC-1α and PPAR-α target gene expression independent of changes in NAD+. Moreover, SIRT1 is required for the induction of PGC-1α/PPAR-α target genes and oxidative metabolism in response to increased ATGL-mediated lipolysis. Taken together, this work identifies SIRT1 as a critical node that links β-adrenergic signaling and lipolysis to changes in the transcriptional regulation of oxidative metabolism.

Lipid droplets (LDs) provide a reservoir for triacylglycerol storage and are a central hub for fatty acid trafficking and signaling in cells. Lipolysis promotes mitochondrial biogenesis and oxidative metabolism via a SIRT1/PGC-1a/PPARa-dependent pathway through an unknown mechanism. Herein, we identify that monounsaturated fatty acids (MUFAs) allosterically activate SIRT1 toward select peptide-substrates such as PGC-1a. MUFAs enhance PGC-1a/ PPARa signaling and promote oxidative metabolism in cells and animal models in a SIRT1-dependent manner. Moreover, we characterize the LD protein perilipin 5 (PLIN5), which is known to enhance mitochondrial biogenesis and function, to be a fattyacid-binding protein that preferentially binds LDderived monounsaturated fatty acids and traffics them to the nucleus following cAMP/PKA-mediated lipolytic stimulation. Thus, these studies identify the first-known endogenous allosteric modulators of SIRT1 and characterize a LD-nuclear signaling axis that underlies the known metabolic benefits of MUFAs and PLIN5.

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Reducing obesity requires an elevation of energy expenditure and/or a suppression of food intake. Here we show that enhancing hepatic glycolysis reduces body weight and adiposity in obese mice. Overexpression of glucokinase or 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is used to increase hepatic glycolysis. Either of the two treatments produces similar increases in rates of fatty acid oxidation in extrahepatic tissues, i.e., skeletal muscle, leading to an elevation of energy expenditure. However, only 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase overexpression causes a suppression of food intake and a decrease in hypothalamic neuropeptide Y expression, contributing to a more pronounced reduction of body weight with this treatment. Furthermore, the two treatments cause differential lipid profiles due to opposite effects on hepatic lipogenesis, associated with distinct phosphorylation states of carbohydrate response element binding protein and AMP-activated protein kinase. The step at which hepatic glycolysis is enhanced dramatically influences overall whole-body energy balance and lipid profiles.

Hepatic steatosis is defined by the accumulation of lipid droplets (LDs). Once thought to be only inert energy storage depots, LDs are increasingly recognized as organelles that have important functions in hepatocytes beyond lipid storage. The lipid and protein composition of LDs is highly dynamic and influences their intrinsic metabolism and signaling properties, which ultimately links them to the changes in hepatic function. This concise review will highlight recent discoveries in LD biology and highlight unique aspects of hepatic LDs and their role in liver disease.