Overexpression of Adiponectin Targeted to Adipose Tissue in Transgenic Mice: Impaired Adipocyte Differentiation

TLDR

Adiponectin is an adipokine whose circulating levels inversely correlate with obesity and insulin resistance, yet the long‑term consequences of its overexpression on body weight remain unclear. The study aimed to generate a transgenic mouse model with persistent, moderate overexpression of native full‑length adiponectin specifically in white adipose tissue to investigate its chronic effects on adiposity and metabolism. The authors created a transgenic mouse line in which the adiponectin gene is driven by a white adipose tissue–specific promoter, enabling sustained, moderate overexpression of full‑length adiponectin within adipocytes. Transgenic mice overexpressing adiponectin in white adipose tissue exhibit reduced fat mass and smaller adipocytes, increased energy expenditure and uncoupling protein expression, impaired adipocyte differentiation marked by loss of lipogenic enzymes and adipocyte markers, and improved insulin sensitivity and lipid profiles.

Abstract

Adiponectin (ApN) is an adipokine whose expression and plasma levels are inversely related to obesity and insulin-resistant states. Chronic repercussions of ApN treatment or overexpression on adiposity and body weight are still controversial. Here, we generated a transgenic (Tg) mouse model allowing persistent and moderate overexpression of native full-length ApN targeted to white adipose tissue. Adipose mass and adipocyte size of Tg mice were reduced despite preserved calorie intake. This reduction resulted from increased energy expenditure and up-regulation of uncoupling proteins, and from abrogation of the adipocyte differentiation program, as shown by the loss of a key lipogenic enzyme and of adipocyte markers. Adipose mass remodeling favors enhanced insulin sensitivity and improved lipid profile of Tg mice. Alteration of the adipocyte phenotype was likely to result from increased expression of the preadipocyte factor-1 and from down-regulation of the transcription factor, CCAAT/enhancer binding protein-α, which orchestrates adipocyte differentiation. We further found that recombinant ApN directly stimulated pre- adipocyte factor-1 mRNA and attenuated CCAAT/enhancer binding protein-α expression in cultured 3T3-F442A cells. Conversely, opposite changes in the expression of these genes were observed in white fat of ApN-deficient mice. Thus, besides enhanced energy expenditure, our work shows that impairment of adipocyte differentiation contributes to the anti-adiposity effect of ApN.