Reduced Energy Expenditure and Increased Inflammation Are Early Events in the Development of Ovariectomy-Induced Obesity

Abstract

Menopause, an age-related loss of ovarian hormone production, promotes increased adiposity and insulin resistance. However, the diet-independent mechanism by which loss of ovarian function promotes increased adipose tissue mass and associated metabolic pathologies remains unclear. To address this question, we monitored food intake and weight gain of ovariectomized (OVX) mice and sham OVX (SHM) mice for 12 wk. Although food intake was similar, OVX mice gained 25% more weight than SHM mice. Moreover, the OVX mice accumulated 4.7- and 4.4-fold more perigonadal and inguinal adipose tissue by weight, respectively, with 4.4-fold (perigonadal, P < 0.001) and 5.3-fold (inguinal, P < 0.01) larger adipocytes and no change in adipocyte cell number. OVX-induced adiposity was coincident with an 18% decrease in metabolic rate during the dark phase (P = 0.001) as well as an 11% decrease during the light phase (P = 0.03). In addition, ambulatory activity levels of OVX mice were decreased only during the dark phase (40%, P = 0.008). OVX mice displayed evidence of immune infiltration and inflammation in adipose tissue, because perigonadal and inguinal adipose depots from OVX mice had increased expression of TNFalpha, iNOS, CD11c, and other hallmarks of adipose tissue inflammation. In contrast, expression of the T cell marker CD3 (3.5-fold, P = 0.03) and Th1 cytokine interferon-gamma (IFNgamma) (2.6-fold, P = 0.02) were elevated in perigonadal but not sc fat. Finally, histology revealed OVX-specific liver hepatic steatosis, coincident with increased PPARgamma gene expression and downstream lipogenic gene expression. In summary, OVX in mice decreases energy expenditure, without altering energy intake, resulting in adipocyte hypertrophy, adipose tissue inflammation, and hepatic steatosis.