Immunometabolic Links between Estrogen, Adipose Tissue and Female Reproductive Metabolism (original) (raw)
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Increased adipose tissue in male and female estrogen receptor-alpha knockout mice
Proceedings of the National Academy of Sciences, 2000
Estrogen regulates the amount of white adipose tissue (WAT) in females, but its role in males and whether WAT effects involve estrogen receptor-␣ (ER␣) or ER were unclear. We analyzed the role of ER␣ in WAT and brown adipose tissue by comparing these tissues in wild-type (WT) and ER␣-knockout (␣ERKO) male and female mice. Brown adipose tissue weight was similar in ␣ERKO and WT males at all ages. Progressive increases in WAT were seen in ␣ERKO males with advancing age. Epididymal, perirenal, and inguinal WAT weighed 139-185% more in ␣ERKO than in WT males by 270-360 days of age. Epididymal and perirenal adipocyte size was increased 20% in ␣ERKO males. Adipocyte number was 82-168% greater in fat pads of ␣ERKO vs. WT males. Compared with WT, 90-day-old ␣ERKO females had increases in fat pad weights (54-103%), adipocyte size, and number. Both ␣ERKO males and females had insulin resistance and impaired glucose tolerance, similar to humans lacking ER␣ or aromatase. Energy intake was equal in WT and ␣ERKO males, indicating that obesity was not induced by hyperphagia. In contrast, energy expenditure was reduced by 11% in ␣ERKO compared with WT males, indicating that altered energy expenditure may be important for the observed obesity. In summary, ER␣ absence causes adipocyte hyperplasia and hypertrophy, insulin resistance, and glucose intolerance in both sexes. These results are evidence that estrogen͞ER␣ signaling is critical in female and male WAT; obesity in ␣ERKO males involves a mechanism of reduced energy expenditure rather than increased energy intake.
Obesity, 2006
SAIRAM, M RAM, MIN WANG, NATALIA DANILOVICH, DANESH JAVESHGHANI, AND DUSICA MAYSINGER. Early obesity and age-related mimicry of metabolic syndrome in female mice with sex hormonal imbalances. Obesity. 2006;14:1142-1154 Objective: To investigate the relationship of early obesity to metabolic syndrome during sex hormonal imbalances in mutant female mice at different ages. Research Methods and Procedures: Hormonal imbalances, accumulation and nature of adipose tissue, food intake, glucose tolerance, and expression of candidate genes and markers of inflammation were studied by comparing wildtype, null, and haploinsufficient follitropin receptor knockout female mice at different ages. Results: Follitropin receptor deletion in mice produced null females that are infertile and haploinsufficient mice that undergo accelerated biological aging. Both types of mutants with sex hormonal imbalances have central obesity without hyperphagia, but circulating leptin is elevated. Adipocyte hyperplasia and hypertrophy is attributed to elevated peroxisome proliferator-activated receptor ␥ expression. Adiponectin protein levels increase in fat tissue and plasma. Only mutants but not controls acquire age-dependent decline in glucose tolerance with high insulin and altered pancreatic  cells. Changes in inflammation markers, decreased muscle insulin receptor phosphorylation, and in-crease of the enzyme protein tyrosine phosphatase 1B indicate insulin resistance. Discussion: In this animal model, the chronological appearance of early obesity induced by hormonal imbalances culminates in characteristics that are attributable to metabolic syndrome, including cardiovascular abnormalities. Dissection of the depot-specific alterations and defining molecular interrelationships could help in developing targeted remedies and resolving complications and controversies related to health benefits and adversities of current hormone replacement therapy.
Endocrinology, 2012
Menopause promotes central obesity, adipose tissue (AT) inflammation, and insulin resistance (IR). Both obesity and the loss of estrogen can activate innate and adaptive immune cells (macrophages, T cells). The respective impacts of weight gain and loss of ovarian hormones on AT inflammation and IR are poorly understood. Here we determined the temporal kinetics of fat accretion, AT inflammation, and IR over a 26-wk time course in ovariectomized (OVX) mice, a model of menopause. OVX and sham-operated (SHM) C57BL6 mice were fed a normal chow diet. Weight, body composition (magnetic resonance imaging), total and regional adiposity, activity, food intake, AT crown-like structures, biohumoral measures, and insulin sensitivity (insulin tolerance testing and homeostatic model assessment) were determined at wk 12, 20, and 26. Macrophages and T cells from perigonadal AT were immunophenotyped by fluorescence-associated cell sorting, and perigonadal adipose tissue (PGAT) gene expression was qu...
Metabolic impact of sex hormones on obesity
Brain Research, 2010
Obesity and its associated health disorders and costs are increasing. Men and postmenopausal women have greater risk of developing complications of obesity than younger women. Within the brain, the hypothalamus is an important regulator of energy homeostasis. Two of its sub-areas, the ventrolateral portion of the ventral medial nucleus (VL VMN) and the arcuate (ARC) respond to hormones and other signals to control energy intake and expenditure. When large lesions are made in the hypothalamus which includes both the VL VMN and the ARC, animals eat more, have reduced energy expenditure, and become obese. The ARC and the VL VMN, in addition to other regions in the hypothalamus, have been demonstrated to contain estrogen receptors. There are two estrogen receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). We and others have previously demonstrated that activation of ERα by estrogens reduces food intake and increases body weight. This review focuses on the relative contribution of activation of ERα by estrogens in the ARC and the VL VMN in the regulation of food intake and body weight. Additionally, estrogen receptors have been found in many peripheral tissues including adipose tissue. Estrogens are thought to have direct effects on adipose tissue and estrogens may provide anti-inflammatory properties both in the periphery and the in the central nervous system (CNS) which may protect women from diseases associated with inflammation. Understanding the mechanisms by which estrogens regulate body weight and inflammation will assist in determining potential therapeutic agents for menopausal women to decrease the propensity of diseases associated with obesity.
Effects of Estrogens on Adipokines and Glucose Homeostasis in Female Aromatase Knockout Mice
PLOS ONE, 2015
The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO) mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2) treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental) adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule) in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα) and interleukin 6 (IL6). Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile.
Molecular Metabolism
Objective: Interleukin (IL)-18 plays a crucial role in maintaining metabolic homeostasis and levels of this cytokine are influenced by gender, age, and sex hormones. The role of gender on IL-18 signaling, however, is unclear. We hypothesized that the presence of female sex hormone could preserve the metabolic phenotype of the IL-18R À/À animals. Methods: We studied female mice with a global deletion of the a isoform of the IL-18 receptor (IL-18R À/À) and littermates control. Three studies were done: 1) animals fed a high fat diet (HFD) for 16 weeks; 2) animals fed chow diet for 72 weeks and 3) animals (3 weeks-old) randomized to either bilateral ovariectomy (OVX) or control surgery (SHAM) and followed for 16 weeks. Results: Female IL-18R À/À mice gained less weight and maintained glucose homeostasis on a chow diet compared with HFD, but no differences between genotypes were observed. The maintenance of body weight and glucose homeostasis in IL-18R À/À mice was lost with aging. By 72 weeks of age, IL-18R À/À mice became heavier compared with WT mice due to an increase in both visceral and subcutaneous adiposity and displayed glucose intolerance. OVX did not affect body weight in IL-18R À/À mice but exacerbated glucose intolerance and impaired liver insulin signaling when compared with SHAM mice. Conclusions: Female mice harboring a global deletion of the IL-18R, only present the same phenotype as reported in male IL-18R À/À mice if they are aged or have undergone OVX, in which circulating estrogen is likely to be blunted. The role of estrogen signaling in the protection against altered metabolic homeostasis in IL-18R À/À mice appears to be mediated by liver insulin signaling. We therefore suggest that the metabolic effects mediated by loss of IL-18 signaling are only present in a female sex hormone free environment.
Obesity and Disturbed Lipoprotein Profile in Estrogen Receptor-α-Deficient Male Mice
Biochemical and Biophysical Research Communications, 2000
Clinical case reports have documented disturbances of carbohydrate and lipid metabolism in aromatase deficient and estrogen resistant males. The aim of the present study was to explore the metabolic functions of estrogens in male mice and to dissect the estrogen receptor (ER) specificity of such effects. Total body fat content and serum levels of leptin were followed in ER␣ knockout (ERKO), ER knockout (BERKO), and ER␣/ double knockout (DERKO) mice. Neither the total body fat nor serum leptin levels were altered in any group before or during sexual maturation. However, after sexual maturation ERKO and DERKO, but not BERKO, demonstrated a clear increase in total body fat and enhanced serum leptin levels. Serum cholesterol was increased and a qualitative change in the lipoprotein profile, including smaller LDL particles, was observed in ERKO and DERKO mice. In conclusion, ER␣ but not ER-inactivated male mice develop obesity after sexual maturation.
Endocrinology, 2013
Estrogen replacement therapy reduces the incidence of type 2 diabetes in postmenopausal women; however, the mechanism is unknown. Therefore, the aim of this study was to evaluate the metabolic effects of estrogen replacement therapy in an experimental model of menopause. At 8 weeks of age, female mice were ovariectomized (OVX) or sham (SHAM) operated, and OVX mice were treated with vehicle (OVX) or estradiol (E2) (OVX+E2). After 4 weeks of high-fat diet feeding, OVX mice had increased body weight and fat mass compared with SHAM and OVX+E2 mice. OVX mice displayed reduced whole-body energy expenditure, as well as impaired glucose tolerance and whole-body insulin resistance. Differences in whole-body insulin sensitivity in OVX compared with SHAM mice were accounted for by impaired muscle insulin sensitivity, whereas both hepatic and muscle insulin sensitivity were impaired in OVX compared with OVX+E2 mice. Muscle diacylglycerol (DAG), content in OVX mice was increased relative to SHAM...
Expansion of intra-abdominal adipose tissue and the accompanying inflammatory response has been put forward as a unifying link between obesity and the development of chronic diseases. However, an apparent sexual dimorphism exists between obesity and chronic disease risk due to differences in the distribution and abundance of adipose tissue. A range of experimental protocols have been employed to demonstrate the role of estrogen in regulating health benefits; however, most studies are confounded by significant differences in body weight and adiposity. Therefore, the purpose of this study was to compare weight-matched obese male and female mice to determine if the sex-dependent health benefits remain when body weight is similar. The development of obesity in female mice receiving a high-fat diet was delayed; however, subsequent comparisons of weight-matched obese mice revealed greater adiposity in obese female mice. Despite excess adiposity and enlarged adipocyte size, obese females remained more glucose tolerant than weight-matched male mice, and this benefit was associated with increased expression of adiponectin and reductions in immune cell infiltration and oxidative stress in adipose tissue. Therefore, the protective benefits of estrogen persist in the obese state and appear to improve the metabolic phenotype of adipose tissue and the individual.