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Background: No sex-specific guidelines for surgical anti-obesity strategies have been proposed, partially due to the controversy regarding sex-related differences in weight loss after bariatric metabolic surgery. Objectives: To explore sex dimorphism in the effect and predictors of weight loss after sleeve gastrectomy (SG), thereby providing clinical evidence for the sex-specific surgical treatment strategy. Methods: In a prospective cohort design, participants scheduled for SG at an affiliated hospital between November 2020 and January 2022 were assessed for eligibility and allocated to the Male or Female group with a 1-year follow-up after surgery. The primary outcome was the sex difference in the weight-loss effect after SG indicated by both percentage of total weight loss (TWL%) and excess weight loss (EWL%). The secondary outcome was the analysis of sex-specific preoperative predictors of weight loss after SG based on univariate and multivariate analyses. Independent predictors were obtained to construct a nomogram model. The discrimination, calibration, and clinical utility of the nomogram were based on receiver operating characteristic curve, concordance index, calibration curve, and decision curve analysis, respectively. Results: Ninety-five male and 226 female patients were initially included. After propensity score matching by baseline body mass index (BMI), 85 male and 143 female patients achieved comparable TWL% and EWL% for 1 year after SG. For male patients, baseline BMI, area under the curve for insulin during oral glucose tolerance test, and progesterone were independent predictors of weight loss after SG. Baseline BMI, age, thyroid stimulating hormone, and Self-Rating Anxiety Scale score were independent predictors for female patients. Conclusion: No obvious sex difference is detected in the weight-loss effect after SG. Sex dimorphism exists in the predictors of weight loss after SG. Further research with long-term and a multicenter design is needed to confirm the predictive model. [ABSTRACT FROM AUTHOR]

The risk of obesity in adulthood is subject to programming in the womb. Maternal obesity contributes to programming of obesity and metabolic disease risk in the adult offspring. With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of maternal high-fat diet (HFD) during pregnancy on offspring's metabolic heath trajectory. In the present study, we determined the long-term metabolic outcomes on adult male and female offspring of dams fed with HFD during pregnancy. C57BL/6J dams were fed either Ctrl or 60% Kcal HFD for 4 weeks before and throughout pregnancy, and we tested glucose homeostasis in the adult offspring. Both Ctrl and HFD-dams displayed increased weight during pregnancy, but HFD-dams gained more weight than Ctrl-dams. Litter size and offspring birthweight were not different between HFD-dams or Ctrl-dams. A significant reduction in random blood glucose was evident in newborns from HFD-dams compared to Ctrl-dams. Islet morphology and alpha-cell fraction were normal but a reduction in beta-cell fraction was observed in newborns from HFD-dams compared to Ctrl-dams. During adulthood, male offspring of HFD-dams displayed comparable glucose tolerance under normal chow. Male offspring re-challenged with HFD displayed glucose intolerance transiently. Adult female offspring of HFD-dams demonstrated normal glucose tolerance but displayed increased insulin resistance relative to controls under normal chow diet. Moreover, adult female offspring of HFD-dams displayed increased insulin secretion in response to high-glucose treatment, but beta-cell mass were comparable between groups. Together, these data show that maternal HFD at pre-conception and during gestation predisposes the female offspring to insulin resistance in adulthood. [ABSTRACT FROM AUTHOR]

Androgens have a complex role in the regulation of insulin sensitivity in the pathogenesis of type 2 diabetes. In male subjects, a reduction in androgens increases the risk for insulin resistance, which is improved by androgen injections. However, in female subjects with polycystic ovary syndrome (PCOS), androgen excess becomes a risk factor for insulin resistance. The exact mechanism underlying the complex activities of androgens remains unknown. In this review, a hormone synergy-based view is proposed for understanding this complexity. Mitochondrial overactivation by substrate influx is a mechanism of insulin resistance in obesity. This concept may apply to the androgen-induced insulin resistance in PCOS. Androgens and estrogens both exhibit activities in the induction of mitochondrial oxidative phosphorylation. The two hormones may synergize in mitochondria to induce overproduction of ATP. ATP surplus in the pancreatic β-cells and α-cells causes excess secretion of insulin and glucagon, respectively, leading to peripheral insulin resistance in the early phase of type 2 diabetes. In the skeletal muscle and liver, the ATP surplus contributes to insulin resistance through suppression of AMPK and activation of mTOR. Consistent ATP surplus leads to mitochondrial dysfunction as a consequence of mitophagy inhibition, which provides a potential mechanism for mitochondrial dysfunction in β-cells and brown adipocytes in PCOS. The hormone synergy-based view provides a basis for the overactivation and dysfunction of mitochondria in PCOS-associated type 2 diabetes. The molecular mechanism for the synergy is discussed in this review with a focus on transcriptional regulation. This view suggests a unifying mechanism for the distinct metabolic roles of androgens in the control of insulin action in men with hypogonadism and women with PCOS. [ABSTRACT FROM AUTHOR]

Androgens have a complex role in the regulation of insulin sensitivity in the pathogenesis of type 2 diabetes. In male subjects, a reduction in androgens increases the risk for insulin resistance, which is improved by androgen injections. However, in female subjects with polycystic ovary syndrome (PCOS), androgen excess becomes a risk factor for insulin resistance. The exact mechanism underlying the complex activities of androgens remains unknown. In this review, a hormone synergy-based view is proposed for understanding this complexity. Mitochondrial overactivation by substrate influx is a mechanism of insulin resistance in obesity. This concept may apply to the androgen-induced insulin resistance in PCOS. Androgens and estrogens both exhibit activities in the induction of mitochondrial oxidative phosphorylation. The two hormones may synergize in mitochondria to induce overproduction of ATP. ATP surplus in the pancreatic β-cells and α-cells causes excess secretion of insulin and glucagon, respectively, leading to peripheral insulin resistance in the early phase of type 2 diabetes. In the skeletal muscle and liver, the ATP surplus contributes to insulin resistance through suppression of AMPK and activation of mTOR. Consistent ATP surplus leads to mitochondrial dysfunction as a consequence of mitophagy inhibition, which provides a potential mechanism for mitochondrial dysfunction in β-cells and brown adipocytes in PCOS. The hormone synergy-based view provides a basis for the overactivation and dysfunction of mitochondria in PCOS-associated type 2 diabetes. The molecular mechanism for the synergy is discussed in this review with a focus on transcriptional regulation. This view suggests a unifying mechanism for the distinct metabolic roles of androgens in the control of insulin action in men with hypogonadism and women with PCOS.

The hypothalamus-pituitary-thyroid-axis (HPT) is one of the main neuroendocrine axes that control energy expenditure. The activity of hypophysiotropic thyrotropin releasing hormone (TRH) neurons is modulated by nutritional status, energy demands and stress, all of which are sex dependent. Sex dimorphism has been associated with sex steroids whose concentration vary along the life-span, but also to sex chromosomes that define not only sexual characteristics but the expression of relevant genes. In this review we describe sex differences in basal HPT axis activity and in its response to stress and to metabolic challenges in experimental animals at different stages of development, as well as some of the limited information available on humans. Literature review was accomplished by searching in Pubmed under the following words: “sex dimorphic” or “sex differences” or “female” or “women” and “thyrotropin” or “thyroid hormones” or “deiodinases” and “energy homeostasis” or “stress”. The most representative articles were discussed, and to reduce the number of references, selected reviews were cited.

Fatty acid binding protein 4 (FABP4) has been associated with insulin resistance. Gestational diabetes mellitus (GDM) impairs fetal insulin sensitivity. Female newborns are more insulin resistant than male newborns. We sought to evaluate the association between GDM and cord blood FABP4, and explore potential sex dimorphic associations and the roles of sex hormones. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns in GDM vs. euglycemic pregnancies matched by infant sex and gestational age at delivery. Cord plasma FABP4, leptin, total and high-molecular-weight adiponectin, testosterone and estradiol concentrations were measured. Adjusting for maternal and neonatal characteristics, cord plasma FABP4 (Mean ± SD: 27.0 ± 19.6 vs. 18.8 ± 9.6 ng/mL, P=0.045) and estradiol (52.0 ± 28.6 vs. 44.2 ± 26.6, ng/mL, P=0.005) concentrations were higher comparing GDM vs. euglycemic pregnancies in males, but similar in females (all P>0.5). Mediation analyses showed that the positive association between GDM and cord plasma FABP4 in males could be partly mediated by estradiol (P=0.03), but not by testosterone (P=0.72). Cord plasma FABP4 was positively correlated with total adiponectin in females (r=0.17, P=0.053), but the correlation was in the opposite direction in males (r=-0.11, P=0.16) (test for difference in r, P=0.02). Cord plasma FABP4 was not correlated with leptin in both sexes. The study is the first to demonstrate sex-dimorphic associations between GDM and cord plasma FABP4 or estradiol, and between FABP4 and adiponectin in newborns. GDM may affect fetal circulating FABP4 and estradiol levels in males only.

The hypothalamus-pituitary-thyroid-axis (HPT) is one of the main neuroendocrine axes that control energy expenditure. The activity of hypophysiotropic thyrotropin releasing hormone (TRH) neurons is modulated by nutritional status, energy demands and stress, all of which are sex dependent. Sex dimorphism has been associated with sex steroids whose concentration vary along the life-span, but also to sex chromosomes that define not only sexual characteristics but the expression of relevant genes. In this review we describe sex differences in basal HPT axis activity and in its response to stress and to metabolic challenges in experimental animals at different stages of development, as well as some of the limited information available on humans. Literature review was accomplished by searching in Pubmed under the following words: "sex dimorphic" or "sex differences" or "female" or "women" and "thyrotropin" or "thyroid hormones" or "deiodinases" and "energy homeostasis" or "stress". The most representative articles were discussed, and to reduce the number of references, selected reviews were cited. [ABSTRACT FROM AUTHOR]

Fatty acid binding protein 4 (FABP4) has been associated with insulin resistance. Gestational diabetes mellitus (GDM) impairs fetal insulin sensitivity. Female newborns are more insulin resistant than male newborns. We sought to evaluate the association between GDM and cord blood FABP4, and explore potential sex dimorphic associations and the roles of sex hormones. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns in GDM vs. euglycemic pregnancies matched by infant sex and gestational age at delivery. Cord plasma FABP4, leptin, total and high-molecular-weight adiponectin, testosterone and estradiol concentrations were measured. Adjusting for maternal and neonatal characteristics, cord plasma FABP4 (Mean ± SD: 27.0 ± 19.6 vs. 18.8 ± 9.6 ng/mL, P=0.045) and estradiol (52.0 ± 28.6 vs. 44.2 ± 26.6, ng/mL, P=0.005) concentrations were higher comparing GDM vs. euglycemic pregnancies in males, but similar in females (all P>0.5). Mediation analyses showed that the positive association between GDM and cord plasma FABP4 in males could be partly mediated by estradiol (P=0.03), but not by testosterone (P=0.72). Cord plasma FABP4 was positively correlated with total adiponectin in females (r=0.17, P=0.053), but the correlation was in the opposite direction in males (r=-0.11, P=0.16) (test for difference in r, P=0.02). Cord plasma FABP4 was not correlated with leptin in both sexes. The study is the first to demonstrate sex-dimorphic associations between GDM and cord plasma FABP4 or estradiol, and between FABP4 and adiponectin in newborns. GDM may affect fetal circulating FABP4 and estradiol levels in males only. [ABSTRACT FROM AUTHOR]