Inhibition of Sebum Production with the Acetyl Coenzyme A Carboxylase Inhibitor Olumacostat Glasaretil.

Olumacostat glasaretil (OG) is a small molecule inhibitor of acetyl coenzyme A (CoA) carboxylase (ACC), the enzyme that controls the first rate-limiting step in fatty acid biosynthesis. Inhibition of ACC activity in the sebaceous glands is designed to substantially affect sebum production, because over 80% of human sebum components contain fatty acids. OG inhibits de novo lipid synthesis in primary and transformed human sebocytes.

Cardiac Ryanodine Receptor (Ryr2)-mediated Calcium Signals Specifically Promote Glucose Oxidation via Pyruvate Dehydrogenase.

Cardiac ryanodine receptor (Ryr2) Ca release channels and cellular metabolism are both disrupted in heart disease. Recently, we demonstrated that total loss of Ryr2 leads to cardiomyocyte contractile dysfunction, arrhythmia, and reduced heart rate. Acute total Ryr2 ablation also impaired metabolism, but it was not clear whether this was a cause or consequence of heart failure.

Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol.

Aims/hypothesis: Leptin has profound glucose-lowering effects in rodent models of type 1 diabetes, and is currently being tested clinically to treat this disease. In addition to reversing hyperglycaemia, leptin therapy corrects multiple lipid, energy and neuroendocrine imbalances in rodent models of type 1 diabetes, yet the precise mechanism has not been fully defined. Thus, we performed metabolic analyses to delineate the downstream metabolic pathway mediating leptin-induced glucose lowering in diabetic mice.

Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo.

Ca(2+) fluxes between adjacent organelles are thought to control many cellular processes, including metabolism and cell survival. In vitro evidence has been presented that constitutive Ca(2+) flux from intracellular stores into mitochondria is required for basal cellular metabolism, but these observations have not been made in vivo. We report that controlled in vivo depletion of cardiac RYR2, using a conditional gene knock-out strategy (cRyr2KO mice), is sufficient to reduce mitochondrial Ca(2+) and oxidative metabolism, and to establish a pseudohypoxic state with increased autophagy.

ATP-citrate lyase reduction mediates palmitate-induced apoptosis in pancreatic beta cells.

Elevated extracellular lipids, such as the free fatty acid palmitate, can induce pancreatic beta cell endoplasmic reticulum (ER) stress and apoptosis, thereby contributing to the initiation and progression of type 2 diabetes. ATP-citrate lyase (ACLY), a key enzyme in cellular lipid production, was identified as a palmitate target in a proteomic screen. We investigated the effects of palmitate on ACLY activity and phosphorylation and its role in beta cell ER stress and apoptosis.