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The steep rise of type 2 diabetes mellitus (T2DM) and associated complications go along with mounting evidence of clinically important sex and gender differences. T2DM is more frequently diagnosed at lower age and body mass index in men; however, the most prominent risk factor, which is obesity, is more common in women. Generally, large sex-ratio differences across countries are observed. Diversities in biology, culture, lifestyle, environment, and socioeconomic status impact differences between males and females in predisposition, development, and clinical presentation. Genetic effects and epigenetic mechanisms, nutritional factors and sedentary lifestyle affect risk and complications differently in both sexes. Furthermore, sex hormones have a great impact on energy metabolism, body composition, vascular function, and inflammatory responses. Thus, endocrine imbalances relate to unfavorable cardiometabolic traits, observable in women with androgen excess or men with hypogonadism. Both biological and psychosocial factors are responsible for sex and gender differences in diabetes risk and outcome. Overall, psychosocial stress appears to have greater impact on women rather than on men. In addition, women have greater increases of cardiovascular risk, myocardial infarction, and stroke mortality than men, compared with nondiabetic subjects. However, when dialysis therapy is initiated, mortality is comparable in both males and females. Diabetes appears to attenuate the protective effect of the female sex in the development of cardiac diseases and nephropathy. Endocrine and behavioral factors are involved in gender inequalities and affect the outcome. More research regarding sex-dimorphic pathophysiological mechanisms of T2DM and its complications could contribute to more personalized diabetes care in the future and would thus promote more awareness in terms of sex- and gender-specific risk factors.

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Sex and Gender Differences in Risk, Pathophysiology and Complications of Type 2 Diabetes Mellitus.

Purpose of Review
The purpose of this review was to summarise current evidence that some environmental chemicals may be able to interfere in the endocrine regulation of energy metabolism and adipose tissue structure.

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Endocrine Disruptors and Obesity

Endocrine Disrupting Chemicals (EDCs) are a global problem for environmental and human health. They are defined as "an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action". It is estimated that there are about 1000 chemicals with endocrine-acting properties. EDCs comprise pesticides, fungicides, industrial chemicals, plasticizers, nonylphenols, metals, pharmaceutical agents and phytoestrogens. Human exposure to EDCs mainly occurs by ingestion and to some extent by inhalation and dermal uptake. Most EDCs are lipophilic and bioaccumulate in the adipose tissue, thus they have a very long half-life in the body. It is difficult to assess the full impact of human exposure to EDCs because adverse effects develop latently and manifest at later ages, and in some people do not present. Timing of exposure is of importance. Developing fetus and neonates are the most vulnerable to endocrine disruption. EDCs may interfere with synthesis, action and metabolism of sex steroid hormones that in turn cause developmental and fertility problems, infertility and hormone-sensitive cancers in women and men. Some EDCs exert obesogenic effects that result in disturbance in energy homeostasis. Interference with hypothalamo-pituitary-thyroid and adrenal axes has also been reported. In this review, potential EDCs, their effects and mechanisms of action, epidemiological studies to analyze their effects on human health, bio-detection and chemical identification methods, difficulties in extrapolating experimental findings and studying endocrine disruptors in humans and recommendations for endocrinologists, individuals and policy makers will be discussed in view of the relevant literature.

Endocrine disrupting chemicals: exposure, effects on human health, mechanism of action, models for testing and strategies for prevention.

This review summarizes recent evidence concerning hormonal and sex chromosome effects in obesity, atherosclerosis, aneurysms, ischemia/reperfusion injury, and hypertension. Cardiovascular diseases occur and progress differently in the 2 sexes, because biological factors differing between the sexes have sex-specific protective and harmful effects. By comparing the 2 sexes directly, and breaking down sex into its component parts, one can discover sex-biasing protective mechanisms that might be targeted in the clinic. Gonadal hormones, especially estrogens and androgens, have long been found to account for some sex differences in cardiovascular diseases, and molecular mechanisms mediating these effects have recently been elucidated. More recently, the inherent sexual inequalities in effects of sex chromosome genes have also been implicated as contributors in animal models of cardiovascular diseases, especially a deleterious effect of the second X chromosome found in females but not in males. Hormonal and sex chromosome mechanisms interact in the sex-specific control of certain diseases, sometimes by opposing the action of the other.

Sex Hormones and Sex Chromosomes Cause Sex Differences in the Development of Cardiovascular Diseases.

Sexual dimorphism in white and brown adipose tissue with obesity and inflammation.

Brown adipose tissue (BAT) is able to rapidly generate heat and metabolise macronutrients, such as glucose and lipids, through activation of mitochondrial uncoupling protein 1 (UCP1). Diet can modulate UCP1 function but the capacity of individual nutrients to promote the abundance and activity of UCP1 is not well established. Caffeine consumption has been associated with loss of body weight and increased energy expenditure, but whether it can activate UCP1 is unknown. This study examined the effect of caffeine on BAT thermogenesis in vitro and in vivo. Stem cell-derived adipocytes exposed to caffeine (1 mM) showed increased UCP1 protein abundance and cell metabolism with enhanced oxygen consumption and proton leak. These functional responses were associated with browning-like structural changes in mitochondrial and lipid droplet content. Caffeine also increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and mitochondrial biogenesis, together with a number of BAT selective and beige gene markers. In vivo, drinking coffee (but not water) stimulated the temperature of the supraclavicular region, which co-locates to the main region of BAT in adult humans, and is indicative of thermogenesis. Taken together, these results demonstrate that caffeine can promote BAT function at thermoneutrality and may have the potential to be used therapeutically in adult humans.

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Caffeine exposure induces browning features in adipose tissue in vitro and in vivo

Obesity remains a major global health concern. Understanding the metabolic influences of the obesity epidemic in the human population on maintenance of a healthy weight and metabolic profile is still of great significance. The importance and role of white adipose tissue has been long established, particularly with excess adiposity. Brown adipose tissue (BAT), however, has only recently been shown to contribute significantly to the metabolic signature of mammals outside the previously recognised role in small mammals and neonates. BAT's detection in adults has led to a renewed interest and is now considered to be a potential therapeutic target to prevent excess white fat accumulation in obesity, a theory further promoted by the recent discovery of beige fat. Adipose tissue distribution varies significantly between genders. Pre-menopausal females often show enhanced lower and peripheral fat deposition in adiposity deposition compared to the male profile of central and visceral fat accumulation with obesity. This sex disparity is partly attributed to the different effects of sex hormone profiles and interactions on the adipose tissue system. In this review, we explore this intricate relationship and show how modifications in the effects of sex hormones impact on both brown and white adipose tissues. We also discuss the impact of sex hormones on activation of the hypothalamic-pituitary-adrenal (HPA) axis and how the three pathways between adiposity, HPA and sex steroids can have a major contribution to the prevention or maintenance of obesity and therefore on overall health.

The influence of sex steroids on adipose tissue growth and function.

Brown and beige adipocytes are characterised as expressing the unique mitochondrial uncoupling protein (UCP)1 for which the primary stimulus in vivo is cold exposure. The extent to which cold-induced UCP1 activation can also be achieved in vitro, and therefore perform a comparable cellular function, is unknown. We report an in vitro model to induce adipocyte browning using bone marrow (BM) derived mesenchymal stem cells (MSC), which relies on differentiation at 32 °C instead of 37 °C. The low temperature promoted browning in adipogenic cultures, with increased adipocyte differentiation and upregulation of adipogenic and thermogenic factors, especially UCP1. Cells exhibited enhanced uncoupled respiration and metabolic adaptation. Cold-exposed differentiated cells showed a marked translocation of leptin to adipocyte nuclei, suggesting a previously unknown role for leptin in the browning process. These results indicate that BM-MSC can be driven to forming beige-like adipocytes in vitro by exposure to a reduced temperature. This in vitro model will provide a powerful tool to elucidate the precise role of leptin and related hormones in hitherto functions in the browning process.

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Low temperature exposure induces browning of bone marrow stem cell derived adipocytes in vitro

Aim: Exercise training elicits diverse effects on brown (BAT) and white adipose tissue (WAT) physiology in rodents housed below their thermoneutral zone (i.e., 28-32°C). In these conditions, BAT is chronically hyperactive and, unlike human residence, closer to thermoneutrality. Therefore, we set out to determine the effects of exercise training in obese animals at 28°C (i.e., thermoneutrality) on BAT and WAT in its basal (i.e., inactive) state. Methods: Sprague-Dawley rats (n = 12) were housed at thermoneutrality from 3 weeks of age and fed a high-fat diet. At 12 weeks of age half these animals were randomized to 4-weeks of swim-training (1 h/day, 5 days per week). Following a metabolic assessment interscapular and perivascular BAT and inguinal (I)WAT were taken for analysis of thermogenic genes and the proteome. Results: Exercise attenuated weight gain but did not affect total fat mass or thermogenic gene expression. Proteomics revealed an impact of exercise training on 2-oxoglutarate metabolic process, mitochondrial respiratory chain complex IV, carbon metabolism, and oxidative phosphorylation. This was accompanied by an upregulation of multiple proteins involved in skeletal muscle physiology in BAT and an upregulation of muscle specific markers (i.e., Myod1, CkM, Mb, and MyoG). UCP1 mRNA was undetectable in IWAT with proteomics highlighting changes to DNA binding, the positive regulation of apoptosis, HIF-1 signaling and cytokine-cytokine receptor interaction. Conclusion: Exercise training reduced weight gain in obese animals at thermoneutrality and is accompanied by an oxidative signature in BAT which is accompanied by a muscle-like signature rather than induction of thermogenic genes. This may represent a new, UCP1-independent pathway through which BAT physiology is regulated by exercise training.

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Ian Bloor

Papers

Sexual dimorphism in white and brown adipose tissue with obesity and inflammation.

Caffeine exposure induces browning features in adipose tissue in vitro and in vivo

The influence of sex steroids on adipose tissue growth and function.

Low temperature exposure induces browning of bone marrow stem cell derived adipocytes in vitro

Exercise Training in Obese Rats Does Not Induce Browning at Thermoneutrality and Induces a Muscle-Like Signature in Brown Adipose Tissue