The role of gender in the progression of fatty liver due to chronic high-fat high-fructose diet (HFFD) has not been studied. The present investigation assessed whether HFFD induced hepatic perturbations differently between the sexes and examined the potential mechanisms. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were fed either a control diet or HFFD for 12 wk. Indexes of liver damage and hepatic steatosis were analyzed biochemically and histologically together with monitoring changes in hepatic gene and protein expression. HFFD induced a higher degree of hepatic steatosis in females, with significant increases in proteins involved in hepatic lipogenesis, whereas HFFD significantly induced liver injury, inflammation, and oxidative stress only in males. Interestingly, a significant increase in hepatic fibroblast growth factor 21 (FGF21) protein expression was observed in HFFD-fed males but not in HFFD-fed females. Ovarian hormone deprivation by itself led to a significant reduction in FGF21 with hepatic steatosis, and HFFD further aggravated hepatic fat accumulation in OVX rats. Importantly, estrogen replacement restored hepatic FGF21 levels and reduced hepatic steatosis in HFFD-fed OVX rats. Collectively, our results indicate that male rats are more susceptible to HFFD-induced hepatic inflammation and that the mechanism underlying this sex dimorphism is mediated through hepatic FGF21 expression. Our findings reveal sex differences in the development of HFFD-induced fatty liver and indicate the protective role of estrogen against HFFD-induced hepatic steatosis.

Background: Ecdysteroids are polyhydroxylated steroids present in invertebrates and plants. 20-Hydroxyecdysone (20E) is the most common and the main biologically active compound of ecdysteroids. Previous studies have demonstrated anabolic and metabolic effects of 20E in mammals. However, it is unknown whether 20E has a positive effect on all aspects of cardiometabolic syndrome. The aims of this study were to investigate the favorable effect and possible underlying mechanisms of 20E in a rat model of cardiometabolic syndrome (CMS) induced by a high-calorie diet combined with female sex hormone deprivation. Methods: 20E (5 mg/kg, 10 mg/kg, or 20 mg/kg) or pioglitazone (PIO) (10 mg/kg) was intragastrically administered to sham-operated Sprague-Dawley female rats and ovariectomized rats fed a high-fat-high-fructose diet (OHFFD) for 8 weeks. The phenotypic characteristics of CMS, including central adiposity, blood pressure, serum lipid profile, glucose tolerance, insulin action on skeletal muscle glucose transport activity and hepatic protein expression, were determined. Results: Some CMS characteristics were improved by 20E treatment. Rats treated with 20E had lower body weight, abdominal fat accumulation than rats treated with vehicle control without changes in total caloric intake and fat-free mass. OHFFD rats exhibited high blood pressure, but 20E-treated rats maintained normal blood pressure with a lower level of low-density lipoprotein (LDL)-cholesterol. Although 20E showed no positive effect on inducing insulin-mediated glucose transport in the skeletal muscle of OHFFD rats, 20E improved whole body glucose homeostasis. Analysis of protein expression in livers from 20E-treated rats revealed significantly increased expression of pAkt Ser⁴⁷³, pFOXO1 Ser²⁵⁶, pAMPKα Thr¹⁷², and FGF21. Conclusion: 20E treatment can alleviate cardiometabolic disorder caused by a high-fat-high-fructose diet and female sex hormone deprivation. In particular, 20E helps improve whole body insulin sensitivity in OHFFD rats, and the mechanisms that underlie this favorable effect are potentially mediated by the activation of AMPK and FGF21. The present study indicates that 20E could be an alternative therapeutic option for the prevention and alleviation of cardiometabolic syndrome.

The role of high fructose ingestion (HFI) in the development of conditions mimicking human metabolic syndrome has mostly been demonstrated in male animals; however, the extent of HFI-induced metabolic alterations in females remains unclear. The present study investigated whether HFI-induced metabolic perturbations differ between sexes and whether HFI aggravates the metabolic disturbances under ovarian hormone deprivation. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were given either water or liquid fructose (10% wt/vol) for 6 wk. Blood pressure, glucose tolerance, insulin-stimulated glucose transport activity and signaling proteins, including insulin receptor (IR), insulin receptor substrate 1 (IRS-1), Akt, Akt substrate of 160 kDa (AS160), AMPKα, JNK, p38 MAPK, angiotensin-converting enzyme (ACE), ANG II type 1 receptor (AT₁R), ACE2, and Mas receptor (MasR) in skeletal muscle, were evaluated. We found that HFI led to glucose intolerance and hypertension in male and OVX rats but not in female rats with intact ovaries. Moreover, HFI did not induce insulin resistance in the skeletal muscle of female and OVX rats but impaired the insulin-stimulated glucose transport activity in the skeletal muscle of male rats, which was accompanied by lower insulin-stimulated IRS-1 Tyr⁹⁸⁹ (44%), Akt Ser⁴⁷³ (30%), and AS160 Ser⁵⁸⁸ (43%), and increases in insulin-stimulated IRS-1 Ser³⁰⁷ (78%), JNK Thr¹⁸³/Tyr¹⁸⁵ (69%), and p38 MAPK Thr¹⁸⁰/Tyr¹⁸² (81%). The results from the present study show sex differences in the development of metabolic syndrome-like conditions and indicate the protective role of female sex hormones against HFI-induced cardiometabolic abnormalities.

Background: Curcuma comosa Roxb. (C. comosa) is an indigenous medicinal herb that has been used in Thailand as a dietary supplement to relieve postmenopausal symptoms. Recently, a novel phytoestrogen, (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol or compound 049, has been isolated and no study thus far has investigated the role of C. comosa in preventing metabolic alterations occurring in estrogen-deprived state. The present study investigated the long-term effects (12 weeks) of C. comosa hexane extract and compound 049 on insulin resistance in prolonged estrogen-deprived rats. Methods: Female Sprague-Dawley rats were ovariectomized (OVX) and treated with C. comosa hexane extract (125 mg, 250 mg, or 500 mg/kg body weight (BW)) and compound 049 (50 mg/kg BW) intraperitoneally three times per week for 12 weeks. Body weight, food intake, visceral fat weight, uterine weight, serum lipid profile, glucose tolerance, insulin action on skeletal muscle glucose transport activity, and GLUT-4 protein expression were determined. Results: Prolonged ovariectomy resulted in dyslipidemia, impaired glucose tolerance and insulin-stimulated skeletal muscle glucose transport, as compared to SHAM. Treatment with C. comosa hexane extract and compound 049, three times per week for 12 weeks, markedly reduced serum total cholesterol and low-density lipoprotein levels, improved insulin sensitivity and partially restored uterine weights in ovariectomized rats. In addition, compound 049 or high doses of C. comosa hexane extract enhanced insulin-mediated glucose uptake in skeletal muscle and increased muscle GLUT-4 protein levels. Conclusions: Treatment with C. comosa and its diarylheptanoid derivative improved glucose and lipid metabolism in estrogen-deprived rats, supporting the traditional use of this natural phytoestrogen as a strategy for relieving insulin resistance and its related metabolic defects in postmenopausal women.

Aim: The purpose of this study was to evaluate hydration status, fluid intake, sweat rate, and sweat sodium concentration in recreational tropical native runners. Methods: A total of 102 males and 64 females participated in this study. Participants ran at their self-selected pace for 30–100 min. Age, environmental conditions, running profiles, sweat rates, and sweat sodium data were recorded. Differences in age, running duration, distance and pace, and physiological changes between sexes were analysed. A p-value cut-off of 0.05 depicted statistical significance. Results: Males had lower relative fluid intake (6 ± 6 vs. 8 ± 7 mL·kg⁻¹·h⁻¹, p < 0.05) and greater relative fluid balance deficit (−13 ± 8 mL·kg⁻¹·h⁻¹ vs. −8 ± 7 mL·kg⁻¹·h⁻¹, p < 0.05) than females. Males had higher whole-body sweat rates (1.3 ± 0.5 L·h⁻¹ vs. 0.9 ± 0.3 L·h⁻¹, p < 0.05) than females. Mean rates of sweat sodium loss (54 ± 27 vs. 39 ± 22 mmol·h⁻¹) were higher in males than females (p < 0.05). Conclusions: The sweat profile and composition in tropical native runners are similar to reported values in the literature. The current fluid replacement guidelines pertaining to volume and electrolyte replacement are applicable to tropical native runners.