Abstract
<jats:p><p dir="ltr">Excess adiposity is associated with insulin resistance and pancreatic b cell dysfunction. Here we show that palmitoylation cycling in white adipose tissue balances insulin sensitivity and insulin secretion. White (WAT) and brown (BAT) adipose tissue ablation of acyl-protein thioesterase 1 (APT1) in mice (APT1-AdipoKO) increased body weight and exacerbated insulin resistance on a high-fat diet. APT1 ablation limited to BAT decreased body weight without affecting insulin resistance/glucose metabolism on a high fat diet. 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 showed increased isoproterenol-stimulated lipolysis compared to control adipocytes. Despite greater insulin resistance, high fat fed APT1-AdipoKO mice had normal glucose tolerance, preserved b 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 b 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 that the palmitoylation status of visceral adipose tissue can protect against glucose intolerance in the setting of sustained insulin resistance by preserving b cell function in mice.</p></jats:p>