Aromatase deficiency in transplanted bone marrow cells improves vertebral trabecular bone quantity, connectivity, and mineralization and decreases cortical porosity in murine bone marrow transplant recipients.

Estradiol is an important regulator of bone accumulation and maintenance. Circulating estrogens are primarily produced by the gonads. Aromatase, the enzyme responsible for the conversion of androgens to estrogen, is expressed by bone marrow cells (BMCs) of both hematopoietic and nonhematopoietic origin.

Central androgen action reverses hypothalamic astrogliosis and atherogenic risk factors induced by orchiectomy and high-fat diet feeding in male mice.

Hypogonadism in males confers elevated cardiovascular disease (CVD) risk by unknown mechanisms. Recent radiological evidence suggests that low testosterone (T) is associated with mediobasal hypothalamic (MBH) gliosis, a central nervous system (CNS) cellular response linked to metabolic dysfunction. To address mechanisms linking CNS androgen action to CVD risk, we generated a hypogonadal, hyperlipidemic mouse model with orchiectomy (ORX) combined with hepatic PCSK9 overexpression.

Vitamin A homeostasis and cardiometabolic disease in humans: lost in translation?

Vitamin A (retinol) is an essential, fat-soluble vitamin that plays critical roles in embryonic development, vision, immunity, and reproduction. Severe vitamin A deficiency results in profound embryonic dysgenesis, blindness, and infertility. The roles of bioactive vitamin A metabolites in regulating cell proliferation, cellular differentiation, and immune cell function form the basis of their clinical use in the treatment of dermatologic conditions and hematologic malignancies.

Evidence of depot-specific regulation of all-trans-retinoic acid biosynthesis in human adipose tissue.

The prevalence of obesity continues to rise, underscoring the need to better understand the pathways mediating adipose tissue (AT) expansion. All-trans-retinoic acid (atRA), a bioactive vitamin A metabolite, regulates adipogenesis and energy metabolism, and, in rodent studies, aberrant vitamin A metabolism appears a key facet of metabolic dysregulation. The relevance of these findings to human disease is unknown, as are the specific enzymes implicated in vitamin A metabolism within human AT.

Sexually Dimorphic Relationships Among Saa3 (Serum Amyloid A3), Inflammation, and Cholesterol Metabolism Modulate Atherosclerosis in Mice.

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Optimizing clinical phenotyping to better delineate the complex relationship between type 2 diabetes and Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia, and its prevalence is increasing rapidly. According to the Alzheimer's Association, over 5 million adults in the United States over the age of 65 years currently have AD, and this number is expected to exceed 13 million by 2050 in the absence of novel, preventative strategies. Epidemiologic studies have implicated the presence of type 2 diabetes mellitus (T2DM) specifically at midlife as a key modifiable risk factor for AD, and AD may increase risk of dysglycemia and T2DM.

Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors.

Background: The cardiovascular (CV) safety of estrogen replacement therapy (ERT) in perimenopausal women remains uncertain. Although exogenous estrogens increase HDL cholesterol (HDL-C), estrogen-mediated effects on alternative metrics of HDL that may better predict CV risk are unknown.

Objective: To determine the effects of transdermal ERT on HDL composition and cholesterol efflux capacity (CEC), as well as the relationships between these metrics and CV risk factors.

Longitudinal changes in plasma sex hormone concentrations correlate with changes in CT-measured regional adiposity among Japanese American men over 10 years.

Objective: Ageing in male adults is typically accompanied by adiposity accumulation and changes in circulating sex hormone concentrations. We hypothesized that an ageing-associated increase in oestrogens and decrease in androgens would correlate with an increase in adiposity.

Design: 10-year prospective, observational study.

Aromatase deficiency in hematopoietic cells improves glucose tolerance in male mice through skeletal muscle-specific effects.

Estrogens are important for maintaining metabolic health in males. However, the key sources of local estrogen production for regulating energy metabolism have not been fully defined. Immune cells exhibit aromatase activity and are resident in metabolic tissues.

Postprandial remodeling of high-density lipoprotein following high saturated fat and high carbohydrate meals.

Background: Humans spend most of the time in the postprandial state, yet most knowledge about high-density lipoproteins (HDL) derives from the fasted state. HDL protein and lipid cargo mediate HDL's antiatherogenic effects, but whether these HDL constituents change in the postprandial state and are affected by dietary macronutrients remains unknown.

Objectives: This study aimed to assess changes in HDL protein and lipid composition after the consumption of a high-carbohydrate or high saturated fat (HSF) meal.

Hypothalamic Gliosis by MRI and Visceral Fat Mass Negatively Correlate with Plasma Testosterone Concentrations in Healthy Men.

Objective: This study aimed to determine whether a relationship was evident between gliosis in the mediobasal hypothalamus (MBH) and plasma testosterone concentrations in men.

Methods: A total of 41 adult men (aged 18-50 years) from 23 twin pairs underwent fasting morning blood draw and brain magnetic resonance imaging. T2 relaxation time was used to quantify gliosis in the MBH and control areas in the putamen and amygdala.

Sex steroids mediate discrete effects on HDL cholesterol efflux capacity and particle concentration in healthy men.

Background: Exogenous testosterone decreases serum concentrations of high-density lipoprotein cholesterol (HDL-C) in men, but whether this alters cardiovascular risk is uncertain.

Objective: To investigate the effects of testosterone and estradiol on HDL particle concentration (HDL-Pima) and metrics of HDL function.

Methods: We enrolled 53 healthy men, 19 to 55 years of age, in a double-blinded, placebo-controlled, randomized trial.

An intracrine view of sex steroids, immunity, and metabolic regulation.

Background: Over the past two decades, parallel recognition has grown of the importance of both sex steroids and immune activity in metabolic regulation. More recently, these discrete areas have been integrated in studies examining the metabolic effects of sex steroid immunomodulation. Implicit in these studies has been a traditional, endocrine model of sex steroid delivery from the gonads to target cells, including immune cells.

Estrogens and Body Weight Regulation in Men.

Our understanding of the metabolic roles of sex steroids in men has evolved substantially over recent decades. Whereas testosterone once was believed to contribute to metabolic risk in men, the importance of adequate androgen exposure for the maintenance of metabolic health has been demonstrated unequivocally. A growing body of evidence now also supports a critical role for estrogens in metabolic regulation in men.

Androgen receptor deficiency in monocytes/macrophages does not alter adiposity or glucose homeostasis in male mice.

Androgen deprivation in men leads to increased adiposity, but the mechanisms underlying androgen regulation of fat mass have not been fully defined. Androgen receptor (AR) is expressed in monocytes/macrophages, which are resident in key metabolic tissues and influence energy metabolism in surrounding cells. Male mice bearing a cell-specific knockout of the AR in monocytes/macrophages (M-ARKO) were generated to determine whether selective loss of androgen signaling in these cells would lead to altered body composition.

Kidney function is associated with an altered protein composition of high-density lipoprotein.

Patients with chronic kidney disease (CKD) exhibit a myriad of metabolic derangements, including dyslipidemia characterized by low plasma concentrations of high-density lipoprotein (HDL)-associated cholesterol. However, the effects of kidney disease on HDL composition have not been comprehensively determined. Here we used a targeted mass spectrometric approach to quantify 38 proteins contained in the HDL particles within a CKD cohort of 509 participants with a broad range of estimated glomerular filtration rates (eGFRs) (CKD stages I-V, and a mean eGFR of 45.

Circulating sex steroids coregulate adipose tissue immune cell populations in healthy men.

Male hypogonadism results in changes in body composition characterized by increases in fat mass. Resident immune cells influence energy metabolism in adipose tissue and could promote increased adiposity through paracrine effects. We hypothesized that manipulation of circulating sex steroid levels in healthy men would alter adipose tissue immune cell populations.

In immune defense: redefining the role of the immune system in chronic disease.

The recognition of altered immune system function in many chronic disease states has proven to be a pivotal advance in biomedical research over the past decade. For many metabolic and mood disorders, this altered immune activity has been characterized as inflammation, with the attendant assumption that the immune response is aberrant. However, accumulating evidence challenges this assumption and suggests that the immune system may be mounting adaptive responses to chronic stressors.

The short-term and long-term effects of bariatric/metabolic surgery on subcutaneous adipose tissue inflammation in humans.

Context: The mechanisms mediating the short- and long-term improvements in glucose homeostasis following bariatric/metabolic surgery remain incompletely understood.

Objective: To investigate whether a reduction in adipose tissue inflammation plays a role in the metabolic improvements seen after bariatric/metabolic surgery, both in the short-term and longer-term.

Design: Fasting blood and subcutaneous abdominal adipose tissue were obtained before (n=14), at one month (n=9), and 6-12months (n=14) after bariatric/metabolic surgery from individuals with obesity who were not on insulin or anti-diabetes medication.

Dose-response effects of sex hormone concentrations on body composition and adipokines in medically castrated healthy men administered graded doses of testosterone gel.

Objective: Serum sex steroid concentrations may alter body composition and glucose homoeostasis in men in a dose-response manner. We evaluated these end-points in healthy men rendered medically castrate through use of a gonadotrophin-releasing hormone antagonist (acyline) with incremental doses of exogenous testosterone (T) gel.

Design: Subjects (n=6-9 per group) were randomly assigned to injections of acyline every 2 weeks plus transdermal T gel (1.

Short-Term Estrogen Withdrawal Increases Adiposity in Healthy Men.

Context: T deprivation increases risk of insulin resistance in men, but whether this risk is independent of changes in body composition is unknown. Further, the metabolic roles of T and its metabolite estradiol have not been clearly defined in men.

Objective: This study sought to establish the effects of selective sex steroid withdrawal on insulin sensitivity in healthy men.

Stable Intraprostatic Dihydrotestosterone in Healthy Medically Castrate Men Treated With Exogenous Testosterone.

Context: Concern exists that T replacement therapy (TRT) might increase the risk of prostate disease. There are limited data regarding the impact of TRT on prostate androgen concentrations.

Objective: Determine the dose-dependent effects of exogenous T administration on intraprostatic androgen concentrations.

An update on testosterone, HDL and cardiovascular risk in men.

Testosterone prescriptions have risen steadily and sharply in the USA despite a lack of clear understanding of the relationship between androgens and cardiovascular disease. In men with increasing age, testosterone levels decline and cardiovascular disease risk goes up. Ties between hypogonadism and cardiovascular disease are suggested by observational data, yet therapy with testosterone replacement has not been shown to mitigate that risk.

Acyl-CoA synthetase 1 is induced by Gram-negative bacteria and lipopolysaccharide and is required for phospholipid turnover in stimulated macrophages.

The enzyme acyl-CoA synthetase 1 (ACSL1) is induced by peroxisome proliferator-activated receptor α (PPARα) and PPARγ in insulin target tissues, such as skeletal muscle and adipose tissue, and plays an important role in β-oxidation in these tissues. In macrophages, however, ACSL1 mediates inflammatory effects without significant effects on β-oxidation. Thus, the function of ACSL1 varies in different tissues.