Impact of Sex on the Therapeutic Efficacy of Rosiglitazone in Modulating White Adipose Tissue Function and Insulin Sensitivity.

Obesity and type 2 diabetes mellitus are global public health issues. Although males show higher obesity and insulin resistance prevalence, current treatments often neglect sex-specific differences. White adipose tissue (WAT) is crucial in preventing lipotoxicity and inflammation and has become a key therapeutic target.

Diabesity alters the protective effects of estrogens on endothelial function through adipose tissue secretome.

Estrogens have a well-known protective role in the development of the metabolic syndrome. Nevertheless, recent epidemiological data question the cardioprotective effect of estrogens in obese and diabetic women. In this context, white adipose tissue (WAT) becomes dysfunctional, which has an impact on the cardiovascular system.

Estrogen Impairs Adipose Tissue Expansion and Cardiometabolic Profile in Obese-Diabetic Female Rats.

It has been reported that 17β-estradiol (E2) can exert beneficial effects against the development of obesity, providing women with a healthier metabolic profile and conferring cardiovascular protection. However, a growing body of evidence questions this role in the context of obesity and diabetes. We focus on the adipose tissue-heart axis to address the question of whether E2 can have metabolically detrimental effects in an obese-diabetic rat model.

Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones.

Cardiovascular disease (CVD) risk shows a clear sexual dimorphism with age, with a lower incidence in young women compared to age-matched men. However, this protection is lost after menopause. We demonstrate that sex-biased sensitivity to the development of CVD with age runs in parallel with changes in G protein-coupled receptor kinase 2 (GRK2) protein levels in the murine heart and that mitochondrial fusion markers, related to mitochondrial functionality and cardiac health, inversely correlate with GRK2.

Sex Differences in Nonalcoholic Fatty Liver Disease: Estrogen Influence on the Liver-Adipose Tissue Crosstalk.

Nonalcoholic fatty liver disease (NAFLD) is a hepatic and systemic disorder with a complex multifactorial pathogenesis. Owing to the rising incidence of obesity and diabetes mellitus, the prevalence of NAFLD and its impact on global health care are expected to increase in the future. Differences in NAFLD exist between males and females, and among females depending on their reproductive status.

17β-estradiol ameliorates lipotoxicity-induced hepatic mitochondrial oxidative stress and insulin resistance.

The prevalence and severity of nonalcoholic fatty liver disease (NAFLD) is higher in men and postmenopausal women compared to premenopausal women, suggesting a protective role for ovarian hormones. Diet-induced obesity and fatty acids surplus promote mitochondrial dysfunction in liver, triggering oxidative stress and activation of c-Jun N-terminal kinase (JNK) which has been related to the development of insulin resistance and steatosis, the main hallmarks of NAFLD. Considering that estrogen, in particular 17β-estradiol (E2), have been reported to improve mitochondrial biogenesis and function in liver, our aim was to elucidate the role of E2 in preventing fatty acid-induced insulin resistance in hepatocytes through modulation of mitochondrial function, oxidative stress and JNK activation.

GPER and ERα mediate estradiol enhancement of mitochondrial function in inflamed adipocytes through a PKA dependent mechanism.

Obesity is associated with inflammation, dysregulated adipokine secretion, and disrupted adipose tissue mitochondrial function. Estradiol (E2) has been previously reported to increase mitochondrial function and biogenesis in several cell lines, but neither the type of oestrogen receptor (ERα, ERβ and GPER) involved nor the mechanism whereby such effects are exerted have been fully described. Considering the anti-inflammatory activity of E2 as well as its effects in enhancing mitochondrial biogenesis, the aim of this study was to investigate the contribution of ERα, ERβ, and GPER signaling to the E2-mediated enhancement of adipocyte mitochondrial function in a pro-inflammatory situation.

17β-estradiol improves hepatic mitochondrial biogenesis and function through PGC1B.

Sexual dimorphism in mitochondrial biogenesis and function has been described in many rat tissues, with females showing larger and more functional mitochondria. The family of the peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1) plays a central role in the regulatory network governing mitochondrial biogenesis and function, but little is known about the different contribution of hepatic PGC1A and PGC1B in these processes. The aim of this study was to elucidate the role of 17β-estradiol (E2) in mitochondrial biogenesis and function in liver and assess the contribution of both hepatic PGC1A and PGC1B as mediators of these effects.

Proteomic study of periovarian adipose tissue in 17β-estradiol-treated and untreated ovariectomized rats.

Taking into account the sexual dimorphism previously found in white adipose tissue (WAT) regarding mitochondrial function and biogenesis, as well as insulin sensitivity, the aim of this study was to go further into the role of sex hormones in this dimorphism. To achieve this objective, we used ovariectomized rats and performed a screening by means of proteomic analyses of the periovarian WAT, combined with a study of the protein levels of specific factors involved in mitochondrial function. Rats were ovariectomized at 5 weeks of age and subcutaneously injected every 48 h with corn-oil (OVX group) or with 17β-estradiol (E2, 10 μg/kg body mass; OVX + E2 group) for 4 weeks prior to sacrifice.

GPER mediates the effects of 17β-estradiol in cardiac mitochondrial biogenesis and function.

Considering the sexual dimorphism described in cardiac mitochondrial function and oxidative stress, we aimed to investigate the role of 17β-estradiol (E2) in these sex differences and the contribution of E2 receptors to these effects. As a model of chronic deprivation of ovarian hormones, we used ovariectomized (OVX) rats, half of which were treated with E2. Ovariectomy decreased markers of cardiac mitochondrial biogenesis and function and also increased oxidative stress, whereas E2 counteracted these effects.

Sex dimorphism in the onset of the white adipose tissue insulin sensitivity impairment associated with age.

The aim of this study was to investigate the time-course response of retroperitoneal white adipose tissue (WAT) insulin and adiponectin signaling pathway intermediates in relation to the systemic age-associated impairment of insulin sensitivity in male and female rats. The main markers of the insulin and adiponectin signaling pathways of the retroperitoneal WAT, as well as of the systemic insulin sensitivity profile of 3-, 9- and 18-month old Wistar rats of both sexes were determined. Our results indicate that age leads to a decrease in the insulin sensitivity in both sexes that agrees with the decline in the levels of the WAT insulin signaling pathway intermediates, the increase in the adiposity index and the rise in the serum insulin resistance markers.

Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle.

Sexual dimorphism has been found in mitochondrial features of skeletal muscle, with female rats showing greater mitochondrial mass and function compared with males. Adiponectin is an insulin-sensitizing adipokine whose expression has been related to mitochondrial function and that is also expressed in skeletal muscle, where it exerts local metabolic effects. The aim of this research was to elucidate the role of sex hormones in modulation of mitochondrial function, as well as its relationship with adiponectin production in rat skeletal muscle.

Opposite effects of 17-β estradiol and testosterone on mitochondrial biogenesis and adiponectin synthesis in white adipocytes.

Sexual dimorphism has been found in both mitochondrial functionality and adiponectin expression in white adipose tissue, with female rats presenting more functional mitochondria than males and greater adiponectin expression. However, little is known about the role of sex hormones in this dimorphism. The aim was to elucidate the role of sex hormones in mitochondrial biogenesis and dynamics and in adiponectin synthesis in white adipocytes, and also to provide new evidence of the link between these processes.

High-fat diet feeding induces sex-dependent changes in inflammatory and insulin sensitivity profiles of rat adipose tissue.

The aim of the study was to determine, in rats of both sexes, the effect of HF diet feeding on the expression of adipokines involved in inflammatory status and insulin sensitivity and on the levels of proteins involved in lipid handling of retroperitoneal adipose tissue. Eight-week-old Wistar rats of both sexes were fed a control diet (2.9% w/w fat) or an HF diet (30% w/w fat) for 14 weeks.

Retroperitoneal white adipose tissue mitochondrial function and adiponectin expression in response to ovariectomy and 17β-estradiol replacement.

Sexual dimorphism has been previously found both in mitochondrial biogenesis and function and in adiponectin expression of retroperitoneal WAT. However, little is known about the E2 effects on WAT mitochondrial function. Accordingly, the aim of this study was to examine in greater depth the role of estrogens in sexual dimorphism.

Sex differences in the effect of high-fat diet feeding on rat white adipose tissue mitochondrial function and insulin sensitivity.

Obesity-induced mitochondrial dysfunction in white adipose tissue (WAT) leads to a dysregulation of adipokine secretion, which is involved in insulin resistance development. Taking into account the sex differences previously found both in mitochondrial function and for the insulin sensitivity profile in different tissues, the aim of this study was to investigate whether a sex-dependent effect of a long-term high-fat diet (HFD) feeding exists on WAT mitochondrial function. Indeed, HFD effects on the levels of the key components of the insulin and adiponectin signaling pathways, and the consequences of these effects on the systemic profile of insulin sensitivity were also studied.

Long-term high-fat-diet feeding induces skeletal muscle mitochondrial biogenesis in rats in a sex-dependent and muscle-type specific manner.

Background: Mitochondrial dysfunction is thought to play a crucial role in the etiology of insulin resistance, in which skeletal muscle is the main tissue contributor. Sex differences in skeletal muscle insulin and antioxidant responses to high-fat-diet (HFD) feeding have been described. The aim of this study was to elucidate whether there is a sex dimorphism in the effects of HFD feeding on skeletal muscle mitochondrial biogenesis and on the adiponectin signaling pathway, as well as the influence of the muscle type (oxidative or glycolytic).

Sex-dependent differences in rat hepatic lipid accumulation and insulin sensitivity in response to diet-induced obesity.

Ectopic deposition of lipids in liver and other extrahepatic tissues alters their function and occurs once adipose tissue fat storage capacity is exceeded. We investigated sexual dimorphism in the effects of dietary obesity on the liver insulin signaling pathway, as well as its connection to differences in hepatic fat accumulation. Ten-week-old Wistar rats of both sexes were fed a standard diet or a high-fat diet for 26 weeks.

Phytotherapy in a rat model of hyperoxaluria: the antioxidant effects of quercetin involve serum paraoxonase 1 activation.

Serum paraoxonase 1 (PON1) has been reported to be an important contributor to the antioxidant and anti-inflammatory activities of HDL, avoiding LDL oxidation. The activity of this enzyme is reduced in patients with renal insufficiency, caused by elevated oxidative stress and disturbances of apolipoprotein metabolism. Therapeutic utilization of antioxidants to control renal oxidative stress may be an effective therapy in renal protection.

Sex-dependent effects of high-fat-diet feeding on rat pancreas oxidative stress.

Objectives: The objective of the study was to investigate whether sex differences in oxidative stress-associated insulin resistance previously reported in rats could be attributed to a possible sex dimorphism in pancreas redox status.

Methods: Fifteen-month-old male and female Wistar rats were fed a control diet or a high-fat diet for 14 weeks. Serum glucose, lipids, and hormone levels were measured.

Effects of ovariectomy and 17-β estradiol replacement on rat brown adipose tissue mitochondrial function.

Taking into account the sexual dimorphism previously reported regarding mitochondrial function and biogenesis in brown adipose tissue, the aim of the present study was to go further into these differences by investigating the effect of ovariectomy and 17-β estradiol (E2) replacement on brown adipose tissue mitochondrial function. In this study, fourteen-week-old control female and ovariectomized female Wistar rats were used. Rats were ovariectomized at 5 weeks of age and were treated every 2 days with placebo (OVX group) or E2 (10 μg/kg) (OVX+E2 group) for 4 weeks before sacrifice.

Isocaloric intake of a high-fat diet modifies adiposity and lipid handling in a sex dependent manner in rats.

Background: High-fat (HF) diet feeding usually leads to hyperphagia and body weight gain, but macronutrient proportions in the diet can modulate energy intake and fat deposition. The mechanisms of fat accumulation and mobilization may differ significantly between depots, and gender can also influence these differences.

Aim: To investigate, in rats of both sexes, the effect of an isocaloric intake of a diet with an unbalanced proportion of macronutrients on fatty acid composition of visceral and subcutaneous adipose tissues and how this is influenced by both dietary fatty acids and levels of proteins involved in tissue lipid handling.

Age-related decline of skeletal muscle insulin sensitivity in rats: effect of sex and muscle type.

Aging is associated with a progressive decline of skeletal muscle function and insulin sensitivity. Sex differences in the insulin response to different physiological situations have been found, leading to the development of type 2 diabetes. The aim of this study was to investigate the changes in insulin sensitivity with age in male and female rats and to elucidate whether there are sex differences in the alteration profiles of systemic insulin sensitivity parameters, adiposity, skeletal muscle oxidative damage, and the insulin signaling pathway.

Long-term high-fat-diet feeding impairs mitochondrial biogenesis in liver of male and female rats.

Background/aims: Mitochondrial biogenesis includes both mitochondrial proliferation and differentiation and its regulation under different physiological conditions is not clear. Given the sexual dimorphism previously found in mitochondrial function, the aim of this study was to investigate the gender-dependent effect of chronic high-fat-diet (HFD) feeding on rat liver mitochondrial function and biogenesis.

Methods: Ten-week old male and female rats were fed a HFD (26% fat) or a control diet (2.

Gender dimorphism in high-fat-diet-induced insulin resistance in skeletal muscle of aged rats.

Muscle resistance to insulin plays a key role in the metabolic dysregulation associated to obesity. A pro-inflammatory and pro-oxidant status has been proposed to be the link between dietary obesity and insulin resistance. Given the gender differences previously found in mitochondrial function and oxidative stress, the aim of the present study was to investigate whether this gender dimorphism leads to differences in the development of high-fat-diet-induced insulin resistance in rat skeletal muscle.