Abstract
BackgroundUnderstanding gender-associated bias in aging and obesity-driven metabolic derangements has been hindered by the inability to model severe obesity in female mice.MethodsHere, using chow- or high fat diet (HFD)-feeding regimens at standard (TS) and thermoneutral (TN) housing temperatures, the latter to model obesity in female mice, we examined the impact of gender and aging on obesity-associated metabolic derangements and immune responsiveness. Analysis included quantification of: (i) weight gain and adiposity; (ii) the development and severity of glucose dysmetabolism and non-alcoholic fatty liver disease (NAFLD); and (iii) induction of inflammatory pathways related to metabolic dysfunction.ResultsWe show that under chow diet feeding regimen, aging was accompanied by increased body weight and white adipose tissue (WAT) expansion in a gender independent manner. HFD feeding regimen in aged, compared to young, male mice at TS, resulted in attenuated glucose dysmetabolism and hepatic steatosis. However, under TS housing conditions only aged, but not young, HFD fed female mice developed obesity. At TN however, both young and aged HFD fed female mice developed severe obesity. Independent of gender or housing conditions, aging attenuated the severity of metabolic derangements in HFD-fed obese mice. Tempered severity of metabolic derangements in aged mice was associated with increased splenic frequency of regulatory T (Treg) cells, Type I regulatory (Tr1)-like cells and circulating IL-10 levels and decreased vigor of HFD-driven induction of inflammatory pathways in adipose and liver tissues.ConclusionOur findings suggest that aging-associated altered immunological profile and inflammatory vigor may play a dominant role in the attenuation of obesogenic diet-driven metabolic dysfunction.
Highlights
Aging, a key risk factor for development of numerous chronic diseases, is linked with weight gain/obesity, Nutrition and DiabetesMoreno-Fernandez et al Nutrition and Diabetes (2021)11:15white adipose tissue (WAT) distribution varies between men and women, with males and post-menopausal women exhibiting increased amounts of visceral fat, while pre-menopausal women exhibit increased amounts of subcutaneous fat[7]
Aging promotes accumulation of peripheral and WAT regulatory T cells that express high levels of CD25 (Tregs) and increased IL-10 production19— immune mediators associated with healthy aging, WAT homeostasis, and insulin-sensitizing effects[20,21]
In this study we aimed to examine the combinatory role of aging and gender-bias on weight gain, development of metabolic derangements, and altered immune responsiveness
Summary
A key risk factor for development of numerous chronic diseases, is linked with weight gain/obesity, Nutrition and DiabetesMoreno-Fernandez et al Nutrition and Diabetes (2021)11:15WAT distribution varies between men and women, with males and post-menopausal women exhibiting increased amounts of visceral fat, while pre-menopausal women exhibit increased amounts of subcutaneous fat[7]. The inability to model robust obesity in C57BL/6 wild type (WT) female mice limits the interrogation of the influence of gender in obesity-driven metabolic derangements[11,12,13]. Such difficulties can be attributed to the housing temperatures ubiquitously employed in mouse husbandry (20–23 °C, standard housing temperature TS) —a temperature range that dramatically alters mouse physiology which dampens animal weight gain and their development of metabolic sequelae. Understanding gender-associated bias in aging and obesity-driven metabolic derangements has been hindered by the inability to model severe obesity in female mice
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