Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity

Authors: ROGERS, NICOLE - JM USDA HNRCA @ TUFTS; PERFIELD, JAMES - JM USDA HNRCA @ TUFTS; STRISSEL, KATHERINE - JM USDA HNRCA @ TUFTS; Obin, Martin; Greenberg, Andrew

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/16/2009
Publication Date: 5/1/2009
Citation: Rogers, N.H., Perfield, J.W., Strissel, K.J., Obin, M., Greenberg, A.S. 2009. Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology. 150(5):2161-8.

Interpretive Summary: While menopause is well-known to be associated with alterations in adiposity and increased risk of metabolic disease, the mechanisms that underlie the increased risk are poorly understood. To address potential mechanisms, we have studied an ovariectomized mouse model of menopause, which allowed us the unique opportunity to assess the effects of loss of ovarian function independent of hyperphagia, which has been reported in prior studies with rats. In the absence of excess energy intake, we found that the increased adiposity associated with ovariectomy is coincident with alterations in energy expenditure and ambulatory activity levels. In addition, we demonstrate that ovariectomy promotes characteristic inflammatory infiltrate in intra-abdominal and subcutaneous adipose tissue, with evidence for T cells, CD11c+ macrophages, and cytokine production. Additionally, ovariectomized mice appear to develop hepatic inflammation associated with steatosis and increased expression of lipogenic genes. These data are significant as they are consistent with a role for adipose tissue inflammation and related metabolic disturbances in the development of metabolic complications in post-menopausal women.

Technical Abstract: Menopause, an age-related loss of ovarian hormone production, promotes increased adiposity and associated metabolic pathologies. However, the diet-independent mechanism(s) by which loss of ovarian function promotes increased adipose tissue mass and insulin resistance remain unclear. We investigated ovariectomized mice (OVX) as a model of menopause to understand the metabolic perturbations associated with loss of ovarian function. Unlike prior experiments with rats, food intake was identical between OVX and sham-ovariectomized (SHM) mice. Despite an absence of hyperphagia, OVX mice still accumulated dramatically more adipose tissue with significantly larger adipocytes. OVX-induced adiposity was coincident with a markedly slower metabolic rate, as well as decreased ambulatory activity levels. Obesity, particularly intra-abdominal, is associated with chronic adipose tissue inflammation which is now implicated in various metabolic disease states. A characterization of inflammatory profiles of adipose tissue from the SHM and OVX mice uncovered novel evidence supporting depot-dependent roles for T cells and CD11c+ macrophages in OVX-associated adipose tissue inflammation. In addition, histology revealed evidence of hepatic lipid accumulation in livers from OVX mice compared to SHM, likely a result of increased lipogenic gene expression. In conclusion, ovariectomy in mice decreases energy expenditure without increasing energy intake, thereby increasing adiposity. Ovariectomy-induced adiposity results in adipose tissue inflammation, an event known to correlate with the onset of obesity-associated metabolic disease and insulin resistance. While independently detrimental, these events would be expected to be exacerbated by life-style factors such as inactivity and increased caloric intake, and to collectively increase the susceptibility of post-menopausal women to metabolic disease.