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

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-alpha, which orchestrates adipocyte differentiation. We further found that recombinant ApN directly stimulated pre- adipocyte factor-1 mRNA and attenuated CCAAT/enhancer binding protein-alpha 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.

Methionine restriction effects on 11β-HSD1 activity and lipogenic/lipolytic balance in F344 rat adipose tissue

“…Adiponectin can activate AMPK, leading to the phosphorylation and inhibition of ACC as well as the induction of fatty acid oxidation in C2C12 myotubes (52). Chronic overexpression of adiponectin in mouse AT reduces fat pad weight as a function of decreased preadipocyte differentiation and adipocyte diameter as well as increased energy expenditure, marked by decreased FAS expression and increased uncoupling protein 2 (53). Considering the known effects of adiponectin on fatty acid storage and oxidation in light of the ability of MR to increase serum adiponectin levels, it is possible that adiponectin contributes importantly to the reduced adipocyte cross-sectional area observed in MR rats.…”

Inflammation and metabolic dysfunction: links to cardiovascular diseases

“…It has been shown to positively influence energy consumption and fatty acid oxidation in muscle and liver, thereby reducing the triglyceride content (264). Transgenic mice overexpressing adiponectin exert an improved lipid profile (15,194). Adiponectin has been suggested to be an important factor modulating the cardiovascular system because of its anti-atherogenic and anti-inflammatory effects.…”

Adiponectin Reduces Plasma Triglyceride by Increasing VLDL Triglyceride Catabolism

“…In adiponectin transgenic mice, although plasma adiponectin is only moderately elevated, plasma TG concentrations are markedly reduced (5)(6)(7). In contrast, hypertriglyceridemia has been reported in adiponectin-deficient mice (8).…”