Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/31/2012
Publication Date: 9/1/2012
Citation: Vieira-Potter, V.J., Strissel, K.J., Xie, C., Chang, E., Bennett, G., Defuria, J., Obin, M.S., Greenberg, A.S. 2012. Adipose tissue inflammation and reduced insulin sensitivity in ovariectomized mice occurs in the absence of increased adiposity. Endocrinology. 153(9):4266-4277. Interpretive Summary: Menopause, or the lack of ovarian hormone production in women, is associated with obesity and metabolic syndrome for reasons that are not fully understood. The accumulation of intra-abdominal fat is associated with inflammation (e.g., the influx of immune cells including macrophages and T lymphocytes). These key immune players have been shown to be mechanistically related to obesity-related metabolic disturbances including systemic insulin resistance and fatty liver in both humans and mice. This study investigated the immune cell changes that occur in the abdominal fat of mice that had their ovaries removed (OVX) and determined how these immune cell changes relate to obesity and insulin resistance over time as compared to control mice (SHM). Body weight, fatness, insulin sensitivity, food intake and activity levels were monitored for 26 weeks. Mice were studied at 12, 20, and 26 weeks to compare for markers of inflammation in fat tissue. It was found that OVX mice had greater inflammation than SHM throughout the study and became insulin resistant relative to SHM by 26 weeks. The insulin resistance in OVX mice was associated with greater immune cell activation, suggesting that immune cell activation, and not fat accumulation per se, precedes the metabolic dysfunction associated with the loss of ovarian hormone production. This study highlights the independent relationship between adipose tissue immune-physiology and age-related hormonal changes in women and points to the necessity for interventions that specifically target fat tissue inflammatory mechanisms.
Technical Abstract: Menopause promotes central obesity, adipose tissue (AT) inflammation and insulin resistance (IR). Both obesity and the loss of estrogen can activate innate and adaptive immune cells (macrophages (M's), T-cells). The respective impacts of weight gain and loss of ovarian hormones on AT inflammation and IR are poorly understood. Here, we determine the temporal kinetics of fat accretion, AT inflammation and IR over a 26-week time course in ovariectomized (OVX) mice, a model of menopause. OVX and sham-operated (SHM) C57BL6 mice were fed a normal chow diet. Wight, body composition (MRI), total and regional adiposity, activity, food intake, AT crown-like structures, biohumoral measures and insulin sensitivity (ITT and HOMA) were determined at weeks 12, 20, 26. M's and T-cells from perigonadal (PG) AT were immunophenotyped by FACS, and PGAT gene expression was quantified by qPCR. OVX mice (~31 g) became fatter than SHM mice (~26 g) by week 12, but mice were equally insulin sensitive. PGAT of OVX mice contained more T-cells but expressed higher levels of M2- M' (Arg-1) and T-cell regulatory (CTLA4) genes. At week 20, both OVX and SHM mice weighted ~35 g and were equally insulin sensitive with comparable amounts of PGAT and total body fat. OVX became less insulin sensitive than SHM by week 26, coincident with down-regulation of PGAT Arg-1 (-20-fold) and CTLA3 (2-fold) and up-regulation of M1/Th1 genes CD11c (+2-fold); IL 12p40 (+2-fold) and IFN-''(+78-fold). Ovarian hormone loss in mice induces PGAT inflammation and IR by mechanisms that can be uncoupled from OVX-induced obesity.