Adipose Tissue Palmitoylation Cycling Mediates Insulin Resistance and Preservation of β-Cell Function in Mice

Excess adiposity is associated with insulin resistance and pancreatic β-cell dysfunction. We show that palmitoylation cycling in white adipose tissue (WAT) balances insulin sensitivity and insulin secretion. WAT and brown adipose tissue (BAT) ablation of acyl-protein thioesterase 1 (APT1) in APT1-deficient (knockout) mice (APT1-AdipoKO) resulted in increased body weight and exacerbated insulin resistance when the mice were fed a high-fat diet (HFD). APT1 ablation limited to BAT decreased body weight without affecting insulin resistance or glucose metabolism in HFD-fed mice. Insulin-stimulated Akt phosphorylation was decreased in gonadal WAT, muscle, and liver of APT1-AdipoKO mice and in APT1 knockdown 3T3-L1 adipocytes. APT1-deficient gonadal WAT adipocytes were enlarged and had increased isoproterenol-stimulated lipolysis compared with control adipocytes. Despite greater insulin resistance, HFD-fed APT1-AdipoKO mice had normal glucose tolerance, preserved β-cell mass, and increased cell-autonomous glucose-stimulated insulin secretion (GSIS). Chow-fed APT1-AdipoKO mice at age 12–14 months had insulin resistance with improved glucose tolerance, increased β-cell mass, and increased cell-autonomous GSIS. Extracellular vesicles prepared from APT1-deficient 3T3-L1 adipocytes increased GSIS in INS-1 cells. These results suggest the palmitoylation status of visceral adipose tissue can protect against glucose intolerance in the setting of sustained insulin resistance in mice by preserving β-cell function. Article Highlights Palmitoylation, the reversible modification of proteins by palmitate, is altered in diabetes. We inactivated acyl protein thioesterase-1 (APT1), a key palmitoylation cycling enzyme, in adipose tissue to study how fat affects systemic metabolism. Given adiposity effects on β-cell failure, we asked if palmitoylation of proteins in fat affects insulin secretion. Adipose APT1-deficient mice had improved glucose metabolism and increased cell-autonomous insulin secretion in two models of insulin resistance, high-fat diet, and aging. Extracellular vesicles from APT1-deficient adipocytes promoted insulin secretion in insulinoma cells. Altering palmitoylation in fat may preserve β-cell function in insulin resistance.