Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with cardiometabolic risk. Although studies have shown that estradiol positively contributes to energy metabolism via estrogen receptor alpha (ERα), its role specifically in the liver is not defined. Therefore, this study aimed to evaluate the effects of ERα overexpression, specifically in the liver in mice fed a high-fat diet (HFD). Methods: Male C57BL/6J mice were divided into four groups, vehicle fed with regular chow (RC) (RC-Vehicle); vehicle fed an HFD (HFD-Vehicle); AAV-treated fed with RC (RC-AAV); and AAV-treated fed an HFD (HFD-AAV), for 6 weeks (8–10 mice per group). AAV was administered intravenously to induce ERα overexpression. Results: We demonstrate that overexpression of ERα in RC-fed mice reduces body fat (28%). These mice show increased oxygen consumption in cultured primary hepatocytes, both in basal (19%) and maximal respiration (34%). In HFD-fed mice, we showed a decrease in hepatic TAG content (43%) associated with improved hepatic insulin sensitivity (145%). Conclusions: From this perspective, our results prove that hepatic ERα signaling is responsible for some of the metabolic protective effects of estrogen in mice. Overexpression of ERα improves hepatocyte mitochondrial function, consequently reducing hepatic lipid accumulation and protecting animals from hepatic steatosis and hepatic insulin resistance. Further investigations will be needed to determine the exact molecular mechanism by which ERα improves hepatic metabolic health.

Menopause is characterized by a reduction in sex hormones in women and is associated with metabolic changes, including fatty liver and insulin resistance. Lifestyle changes, including a balanced diet and physical exercise, are necessary to prevent these undesirable changes. Strength training (ST) has been widely used because of the muscle and metabolic benefits it provides. Our study aims to evaluate the effects of ST on hepatic steatosis and insulin resistance in ovariectomized mice fed a high-fat diet (HFD) divided into four groups as follows: simulated sedentary surgery (SHAM-SED), trained simulated surgery (SHAM-EXE), sedentary ovariectomy (OVX-SED), and trained ovariectomy (OVX-EXE). They were fed an HFD for 9 weeks. ST was performed thrice a week. ST efficiently reduced body weight and fat percentage and increased lean mass in OVX mice. Furthermore, ST reduced the accumulation of ectopic hepatic lipids, increased AMPK phosphorylation, and inhibited the de novo lipogenesis pathway. OVX-EXE mice also showed a better glycemic profile, associated with greater insulin sensitivity identified by the euglycemic–hyperinsulinemic clamp, and reduced markers of hepatic oxidative stress compared with sedentary animals. Our data support the idea that ST can be indicated as a non-pharmacological treatment approach to mitigate metabolic changes resulting from menopause.

The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), is higher in men than in women of reproductive age, and postmenopausal women are especially susceptible to developing the disease. Aim: we evaluated if female apolipoprotein E (ApoE) KO mice were protected against Western-diet (WD)-induced NASH. Methods: Female ovariectomized (OVX) ApoE KO mice or sham-operated (SHAM) mice were fed either a WD or a regular chow (RC) for 7 weeks. Additionally, OVX mice fed a WD were treated with either estradiol (OVX + E2) or vehicle (OVX). Results: Whole-body fat, plasma glucose, and plasma insulin were increased and associated with increased glucose intolerance in OVX mice fed a WD (OVX + WD). Plasma and hepatic triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) hepatic enzymes were also increased in the plasma of OVX + WD group, which was associated with hepatic fibrosis and inflammation. Estradiol replacement in OVX mice reduced body weight, body fat, glycemia, and plasma insulin associated with reduced glucose intolerance. Treatment also reduced hepatic triglycerides, ALT, AST, hepatic fibrosis, and inflammation in OVX mice. Conclusions: These data support the hypothesis that estradiol protects OVX ApoE KO mice from NASH and glucose intolerance.

Growth hormone (GH) has several metabolic effects, including a profound impact on glucose homeostasis. For example, GH oversecretion induces insulin resistance and increases the risk of developing diabetes mellitus. Here, we show that GH receptor (GHR) ablation in vesicular glutamate transporter 2 (VGLUT2)-expressing cells, which comprise a subgroup of glutamatergic neurons, led to a slight decrease in lean body mass without inducing changes in body adiposity. VGLUT2 ^∆GHR mice exhibited reduced glycemia and improved glucose tolerance and insulin sensitivity. Among different glutamatergic neuronal populations, we found that GHR inactivation in Sim1-expressing cells recapitulated the phenotype observed in VGLUT2 ^∆GHR mice. Furthermore, Sim1 ^∆GHR mice exhibited reduced endogenous glucose production and improved hepatic insulin sensitivity without alterations in whole-body or muscle glucose uptake. Sim1 ^∆GHR mice were protected against acute but not chronic diabetogenic effects of exogenous GH administration. Pharmacological activation of ATP-sensitive potassium channels in the brain normalized blood glucose levels in Sim1 ^∆GHR mice. In conclusion, the absence of GHR signaling in VGLUT2/Sim1-expressing cells causes a persistent reduction in glycemia and improves hepatic insulin sensitivity. Central glucose-sensing mechanisms are likely involved in the reduced glycemia exhibited by Sim1 ^∆GHR mice. The current findings uncover a mechanism involved in the effects of GHR signaling in regulating glucose homeostasis.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by hepatic steatosis, inflammation, fibrosis, and metabolic dysfunction, with limited therapeutic options currently available. This study investigated whether pharmacological inhibition of Galectin-3 (Gal-3), a β-galactoside-binding lectin implicated in inflammation and fibrosis, using modified citrus pectin (MCP), attenuates established MASH in ApoE-deficient mice. Mice were assigned to four groups: standard chow (CTL), standard chow plus MCP (CTL + MCP), Western diet with fructose-enriched drinking water (WD), and WD plus MCP (WD + MCP). MCP (1% in drinking water) was administered during the final four weeks of the 11-week experimental protocol, after the establishment of metabolic dysfunction and hepatic steatosis. Compared with untreated WD mice, WD + MCP mice exhibited improved glucose tolerance, as evidenced by a 22.9% reduction in glucose area under the curve (p = 0.01), and enhanced hepatic insulin signaling, reflected by a 254.1% increase in insulin-stimulated AKT2 phosphorylation (p = 0.0002). MCP treatment also reduced hepatic lipid accumulation (39.8%, p = 0.0055) and hepatic triglyceride content (26.1%, p = 0.0003), accompanied by reductions in circulating triglyceride and cholesterol concentrations. Furthermore, WD + MCP mice exhibited reduced hepatic Gal-3 expression (25.8%, p = 0.0199), decreased F4/80 immunoreactivity (49.2%, p = 0.0061), attenuated JNK phosphorylation (46.6%, p = 0.0118), reduced collagen deposition (47.0%, p = 0.0002), and lower plasma ALT (52.9%, p = 0.0009) and AST (48.8%, p = 0.04) activities. Collectively, these findings demonstrate that MCP attenuates multiple metabolic, inflammatory, fibrotic, and hepatic injury features of established Western diet-induced MASH, supporting Gal-3 as a promising therapeutic target and MCP as a potential pharmacological strategy for MASH.