Background: Acyl-CoA synthetase 1 (ACSL1) promotes inflammatory effects in macrophages, but its regulation and biological role remain largely unknown. Results: Multiple inflammatory pathways contribute to ACSL1 induction, and this induction allows for phospholipid turnover in activated macrophages. Conclusion:The regulation and function of ACSL1 differ substantially in macrophages and insulin target tissues. Significance: These findings indicate a novel role for ACSL1 in innate immunity.

BackgroundRestraint stress has been shown to elicit numerous effects on hippocampal function and neuronal morphology, as well as to induce dendritic remodeling in the prefrontal cortex (PFC). However, the effects of acute restraint stress on PFC cognitive function have not been investigated, despite substantial evidence that the PFC malfunctions in many stress-related disorders.MethodsThe present study examined the effects of restraint stress on PFC function in both male rats and cycling female rats in either the proestrus (high estrogen) or estrus (low estrogen) phase of the estrus cycle. Animals were restrained for 60 or 120 minutes and then tested on spatial delayed alternation, a PFC-mediated task. Performance after stress was compared to performance on a different day under no-stress conditions, and analyzed using analysis of variance (ANOVA).ResultsSixty minutes of restraint impaired only females in proestrus, while 120 minutes of restraint produced significant impairments in all animals. Increases in task completion times did not affect performance.ConclusionThese results demonstrate an interaction between hormonal status and cognitive response to stress in female rats, with high estrogen levels being associated with amplified sensitivity to stress. This effect has been previously observed after administration of a pharmacological stressor (the benzodiazepine inverse agonist FG7142), and results from both studies may be relevant to the increased prevalence of stress-related disorders, such as major depressive disorder, in cycling women. Overall, the results show that restraint stress has important effects on the cognitive functions of the PFC, and that hormonal influences in the PFC are an important area for future research.

BackgroundOver 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. Thus, research to date has focused on the metabolic effects of sex steroid receptor signaling in immune cells. This endocrine model, however, overlooks the extensive capacity of immune cells to generate and metabolize sex steroids, enabling the production of sex steroids for intracrine signaling – that is, sex steroid production for signaling within the cell of origin. Intracrine function allows highly cell-autonomous regulation of sex steroid exposure, and sex steroid secretion by immune cells could confer paracrine signaling effects in neighboring cells within metabolic tissues. In this review, immune cell intracrinology will denote sex steroid production within immune cells for either intracrine or paracrine signaling. This intracrine capacity of immune cells has been well established, and prior work has supported its importance in autoimmune disorders, trauma, and cancer. The potential relevance of immune cell intracrine function to the regulation of energy balance, body weight, body composition, and insulin sensitivity has yet to be explored.Scope of reviewThe following review will detail findings to date regarding the steroidogenic and steroid metabolizing capacity of immune cells, the regulation of immune cell intracrine function, and the biological effects of immune-derived sex steroids, including the clinical relevance of immune cell intracrinology in fields other than metabolism. These findings will serve as the basis for a proposed model of immune cell intracrinology constituting a new frontier in metabolism research.Major conclusionsThe development of highly sensitive mass spectrometric methods for sex steroid measurement and quantitation of metabolic flux now allows unprecedented ability to interrogate sex steroid production, metabolism and secretion by immune cells. Immune cell intracrinology could reveal key mechanisms underlying immune cell-mediated metabolic regulation.

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 6–12 months (n=14) after bariatric/metabolic surgery from individuals with obesity who were not on insulin or anti-diabetes medication. Adipose tissue inflammation was assessed by a combination of whole-tissue gene expression and flow cytometry-based quantification of tissue leukocytes. Results One month after surgery, body weight was reduced by 13.5±4.4 kg (p<0.001), with improvements in glucose tolerance reflected by a decrease in area-under-the-curve (AUC) glucose in 3-h oral glucose tolerance tests (−105±98 mmol/L*min; p=0.009) and enhanced pancreatic β-cell function (insulinogenic index: +0.8±0.9 pmol/mmol; p=0.032), but no change in estimated insulin sensitivity (Matsuda insulin sensitivity index [ISI]; p=0.720). Furthermore, although biomarkers of systemic inflammation and pro-inflammatory gene expression in adipose tissue remained unchanged, the number of neutrophils increased in adipose tissue 15–20 fold (p<0.001), with less substantial increases in other leukocyte populations. By the 6–12 month follow-up visit, body weight was reduced by 34.8±10.8 kg (p<0.001) relative to baseline, and glucose tolerance was further improved (AUC glucose −276±229; p<0.001) along with estimated insulin sensitivity (Matsuda ISI: +4.6±3.2; p<0.001). In addition, improvements in systemic inflammation were reflected by reductions in circulating C-reactive protein (CRP; −2.0±5.3 mg/dL; p=0.002), and increased serum adiponectin (+1,358±1,406 pg/mL; p=0.003). However, leukocyte infiltration of adipose tissue remained elevated relative to baseline, with pro-inflammatory cytokine mRNA expression unchanged, while adiponectin mRNA expression trended downward (p=0.069). Conclusion Both the short- and longer-term metabolic improvements following bariatric/metabolic surgery occur without significant reductions in measures of adipose tissue inflammation, as assessed by measuring the expression of genes encoding key mediators of inflammation and by flow cytometric immunophenotyping and quantification of adipose tissue leukocytes.

Objective In men with prostate cancer, androgen deprivation reduces insulin sensitivity; however, the relative roles played by testosterone and estradiol are unknown. To investigate the respective effects of these hormones on insulin sensitivity in men, we employed a model of experimental hypogonadism with or without hormone replacement. Design Placebo-controlled, randomized trial. Participants 22 healthy male volunteers, 18–55 years old. Methods Following screening, subjects received the gonadotropin releasing hormone antagonist acyline plus one of the following for 28 days: Group 1, placebo transdermal gel and placebo pills; Group 2, transdermal testosterone gel 10g/day plus placebo pills; Group 3, transdermal testosterone gel 10 g/day plus the aromatase inhibitor anastrozole 1 mg/day to normalize testosterone while selectively reducing serum estradiol. Fasting insulin, glucose, adipokines and hormones were measured bi-weekly. Results With acyline administration, serum testosterone was reduced by >90% in all subjects in Group 1. In these men, mean fasting insulin concentrations were significantly increased compared with baseline (p=0.02) at 28 days, despite stable body weight and no changes in fasting glucose concentrations. Decreased insulin sensitivity also was apparent in the insulin sensitivity indices HOMA-IR (p=0.03) and QUICKI (p=0.04). In contrast, in Groups 2 and 3, testosterone concentrations remained in the physiologic range, despite significant reduction in mean estradiol in Group 3. In these groups, no significant changes in insulin sensitivity were observed. Conclusions Acute testosterone withdrawal reduces insulin sensitivity in men independent of changes in body weight, whereas estradiol withdrawal has no effect. Testosterone appears to maintain insulin sensitivity in normal 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. Recent data from clinical intervention studies indicate that estradiol may be a stronger determinant of adiposity than testosterone in men, and even short-term estradiol deprivation contributes to fat mass accrual. The following chapter will outline findings to date regarding the mechanisms whereby estrogens contribute to the regulation of body weight and adiposity in men. It will present emergent clinical data as well as preclinical findings that reveal mechanistic insights into estrogen-mediated regulation of body composition. Findings in both males and females will be reviewed, to draw comparisons and to highlight knowledge gaps regarding estrogen action specifically in males. Finally, the clinical relevance of estrogen exposure in men will be discussed, particularly in the context of a rising global prevalence of obesity and expanding clinical use of sex steroid-based therapies in men.

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 (eGFR) (CKD stages I-V, and a mean eGFR of 45.5 mL/min/1.73m2). After adjusting for multiple testing, demographics, comorbidities, medications, and other characteristics, eGFR was significantly associated with differences in four HDL proteins. Compared to participants with an eGFR of 60 mL/min/1.73m2 or more, those with an eGFR under 15 mL/min/1.73m2 exhibited 1.89-fold higher retinol binding protein 4 (95% confidence interval 1.34-2.67), 1.52-fold higher apolipoprotein C-III (1.25-1.84),0.70-fold lower apolipoprotein L1 (0.55-0.92), and 0.64-fold lower vitronectin (0.48- 0.85). Although the HDL apolipoprotein L1 was slightly lower among African-American than among Caucasian individuals, the relationship to eGFR did not differ by race. After adjustment, no HDL-associated proteins associated with albuminuria. Thus, modest changes in the HDL proteome provide preliminary evidence for an association between HDL proteins and declining kidney function, but this needs to be replicated. Future analyses will determine if HDL proteomics is indeed a clinical predictor of declining kidney function or cardiovascular outcomes.

Objective: To determine whether a relationship was evident between gliosis in the mediobasal hypothalamus (MBH) and plasma testosterone concentrations in men Methods: 41 adult men (ages 18–50 years) from 23 twin pairs underwent fasting morning blood draw and brain MRI. T2 relaxation time was used to quantify gliosis in the MBH and control areas in the putamen and amygdala. Plasma concentrations of testosterone and 17β-estradiol were measured by LC-MS/MS. Body composition including visceral adiposity was measured by dual X-ray absorptiometry. Results: A negative association was found between MBH T2 relaxation time and plasma concentrations of both free and total testosterone ( r = −0.29, P<0.05 and r = −0.37, P<0.01, respectively). Visceral adiposity exhibited a negative correlation with plasma total testosterone concentration ( r = −0.45, P=0.001) but a positive correlation with MBH T2 relaxation time ( r = 0.24, P=0.03). The negative correlation between plasma total testosterone and MBH T2 relaxation time remained significant after adjustment for visceral adiposity, age, BMI, and insulin resistance. Conclusions: In healthy men across a range of BMIs, MBH gliosis was associated with higher visceral adiposity but lower endogenous testosterone. These findings suggest that MBH gliosis could provide novel mechanistic insights into gonadal dysfunction in men with obesity.