Sexual Dimorphism in the Age-Induced Insulin Resistance, Liver Steatosis, and Adipose Tissue Function in Rats

Abstract

Age-linked metabolic disturbances, such as liver steatosis and insulin resistance, show greater prevalence in men than in women. Thus, our aim was to analyze these sex-related differences in male and female Wistar rats (aged 26 days and 3, 7, and 14 months), and to assess their potential relationship with alterations in the capacity of adipose tissue expansion and the dysregulation of the main adipokines produced by the adipose tissue, leptin and adiponectin. Adiposity-related parameters, blood parameters, the expression of genes related to expandability and inflammation (WAT), lipid metabolism (liver), and leptin and insulin signaling (both tissues) were measured. In females, adiposity index and WAT DNA content gradually increased with age, whereas males peaked at 7 months. A similar sex-dependent pattern was observed for leptin expression in WAT, while Mest expression levels decreased with age in males but not in females. Females also showed increased expression of the proliferation marker PCNA in the inguinal WAT compared to males. In males, leptin/adiponectin ratio greatly increased from 7 to 14 months in a more acute manner than in females, along with an increase in HOMA-IR index and hepatic triacylglyceride content, while no changes were observed in females. In liver, 14-month-old males displayed decreased mRNA levels of Insr, Ampkα2, and Cpt1a compared with levels at 7 months. Males also showed decreased mRNA levels of Obrb (both tissues), and increased expression levels of Cd68 and Emr1 (WAT) with age. In conclusion, females are more protected from age-related metabolic disturbances, such as insulin resistance, hepatic lipid deposition, and WAT inflammation compared to males. This may be related to their greater capacity for WAT expansion—reflected by a greater Mest/leptin mRNA ratio—and to their ability to maintain adiponectin levels and preserve leptin sensitivity with aging.

Sexual dimorphism of liver endoplasmic reticulum stress susceptibility in prepubertal rats and the effect of sex steroid supplementation

“…Oestradiol protects against an increase in body adiposity through its effects on appetite suppression and increased energy expenditure (Pedersen, Bruun, Kristensen, & Richelsen, ; Musatov et al., ). Our data are in agreement with the literature (Garcia‐Carrizo, Priego, Szostaczuk, Palou, & Picó, ): in the prepubertal period, there is no sexual dimorphism in the body mass or the mass of the tissues evaluated. On the other hand, in adulthood, when the metabolism of animals is strongly influenced by sex hormones, adult males presented significantly greater body mass than adult females, as well as a heavier liver and greater amount of inguinal and retroperitoneal fat.…”

“…Oestradiol protects against an increase in body adiposity through its effects on appetite suppression and increased energy expenditure (Pedersen, Bruun, Kristensen, & Richelsen, 2001;Musatov et al, 2007). Our It is well known that, in humans and rodents, ageing is associated with an increased risk of insulin resistance, but this association is more pronounced in males than in females (Frias et al, 2001;Garcia-Carrizo et al, 2017;Krotkiewski, Bjorntorp, Sjostrom, & Smith, 1983;Marucci et al, 2015;ter Horst et al, 2015). We did not observe any differences in glycaemia, insulinaemia, HOMA-IR and QUICKI indices between males and females, either in prepubertal or in young adult rats.…”

“…It is well known that, in humans and rodents, ageing is associated with an increased risk of insulin resistance, but this association is more pronounced in males than in females (Frias et al., ; Garcia‐Carrizo et al., ; Krotkiewski, Bjorntorp, Sjostrom, & Smith, ; Marucci et al., ; ter Horst et al., ). We did not observe any differences in glycaemia, insulinaemia, HOMA‐IR and QUICKI indices between males and females, either in prepubertal or in young adult rats.…”

The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing

“…Consistent with the sexual dimorphism in the decline of tissue homeostasis resulting in metabolic and immune response dysfunction during ageing [54][55][56], our survival and cross-sectional intervention studies have highlighted that ES-62 differentially targets distinct pathophysiological responses during HCD-accelerated ageing in male and female mice. To distinguish the key protective healthspan signatures in each sex and to address identifying the factors associated with the ability of ES-62 to extend median lifespan in male HCD-fed mice, we have subjected our multidimensional data sets (120 pathophysiological, immunological and metabolic variables assayed on individual mice in this study) to unsupervised mathematical modelling and statistical analysis.…”

Sex differences in the response to dietary restriction in rodents

“…While the molecular mechanism underlying these sex differences is not known, it is plausible to attribute these differences at least in part to sex hormones. Indeed, estrogen removal in animals or menopause in women is associated with metabolic disturbances including hepatic triglyceride accumulation and decreased insulin sensitivity [39]. …”