Female Mice are Protected against High-Fat Diet Induced Metabolic Syndrome and Increase the Regulatory T Cell Population in Adipose Tissue

Abstract

Sex differences in obesity-induced complications such as type 2 diabetes have been reported. The aim of the study was to pinpoint the mechanisms resulting in different outcome of female and male mice on a high-fat diet (HFD). Mice fed control or HFD were monitored for weight, blood glucose, and insulin for 14 weeks. Circulating chemokines, islet endocrine function and blood flow, as well as adipose tissue populations of macrophages and regulatory T-lymphocytes (Treg) were thereafter assessed. Despite similar weight (43.8±1.0 and 40.2±1.5 g, respectively), male but not female mice developed hyperinsulinemia on HFD as previously described (2.5±0.7 and 0.5±0.1 pmol/l, respectively) consistent with glucose intolerance. Male mice also exhibited hypertrophic islets with intact function in terms of insulin release and blood perfusion. Low-grade, systemic inflammation was absent in obese female but present in obese male mice (IL-6 and mKC, males: 77.4±17 and 1795±563; females: 14.6±4.9 and 240±22 pg/ml), and the population of inflammatory macrophages was increased in intra-abdominal adipose tissues of high-fat-fed male but not female mice. In contrast, the anti-inflammatory Treg cell population increased in the adipose tissue of female mice in response to weight gain, while the number decreased in high-fat-fed male mice. In conclusion, female mice are protected against HFD-induced metabolic changes while maintaining an anti-inflammatory environment in the intra-abdominal adipose tissue with expanded Treg cell population, whereas HFD-fed male mice develop adipose tissue inflammation, glucose intolerance, hyperinsulinemia, and islet hypertrophy.

RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality

“…This longevity effect is independent of sex and diet. It also is worth noting that when fed a high-cholesterol diet, young female mice were more protected than young males, similar to observations in humans (29).…”

Differences in Hematopoietic Stem Cells Contribute to Sexually Dimorphic Inflammatory Responses to High Fat Diet-induced Obesity

“…Our findings show that sex differences in myeloid cell production and maturation of proinflammatory ATMs are one factor that may explain prior observations. Despite similar adipocyte hypertrophy, female mice are protected from inflammatory changes in adipose tissue similar to other reports (29,30). Given that short and long term HFD studies cannot distinguish whether the enhanced ATM myeloid activation in male mice is merely due to the increase in adiposity and lower energy expenditure or to insulin resistance seen in males compared with females, we performed a competitive BMT experiment that permitted us to compare myeloid cell activation between sexes in the same recipient.…”

High-fat diet-induced β-cell proliferation occurs prior to insulin resistance in C57Bl/6J male mice

“…The sex of the mice was another factor taken into consideration. We chose male mice because, although both male and female mice experience similar weight gain on HFD, glucose tolerance and insulin secretion are more severely impaired in males, whereas ␤-cell mass in females is resistant to the effects of HFD (14,29).…”