Loss of lysyl oxidase in adipose tissue ameliorates metabolic inflexibility induced by high-fat diet.

Abstract

Systemic administration of β-aminopropionitrile to inhibit lysyl oxidase (Lox) activity improves metabolism, but it exhibits a broad spectrum of effects. Clarification of the role of Lox in adipose tissue metabolism under high-fat diet (HFD) conditions is needed. Mice with adipose tissue knockout of Lox (Lox^AKO) and wild-type mice were subjected to a 16-week HFD regimen. A detailed evaluation encompassing adipose tissue, hepatic function, and systemic metabolism was conducted. RNA sequencing analysis was used to unravel the intricate mechanisms behind the metabolic enhancements in Lox^AKO mice. Compared with the control, although there was no difference in body weight, Lox^AKO mice exhibited an improved metabolic phenotype, including enhanced insulin sensitivity, improved glucose tolerance, and reduced liver steatosis, along with reduced adipose tissue inflammation and fibrosis. Lox^AKO mice showed increased thermogenic activity in brown adipose tissue with increased uncoupling protein 1 (UCP1) expression and oxygen consumption rate. Additionally, RNA sequencing analysis revealed that adipose deletion of Lox might facilitate the metabolic processing of glucose, branched-chain amino acids, and fatty acids in brown adipose tissue. These findings indicate that adipocyte Lox deletion improves metabolic adaptability under an HFD, highlighting Lox as a promising therapeutic target for obesity-associated metabolic disorders.