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FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is a key regulator of glucocorticoid signaling and has been implicated in metabolism and insulin sensitivity, but its specific role in human adipose tissue remains unclear. This study investigated the role of FKBP51 in human adipose tissue and its impact on glucose metabolism and insulin signaling. FKBP5 was measured in paired subcutaneous (SAT) and omental (OAT) adipose tissue samples from 56 subjects with and without obesity, and in SAT from individuals with obesity during weight loss up to 104 weeks post-bariatric surgery. Furthermore, FKBP51 knockdown adipocytes were used to study its effects on insulin signaling and glucose uptake. FKBP5 gene expression, but not protein expression, was significantly lower in obese individuals in both SAT and OAT compared to lean and overweight subjects, and it inversely correlated with insulin resistance measured by homeostatic model assessment of insulin resistance (HOMA-IR). After bariatric surgery, FKBP5 expression in SAT increased to levels similar to those in non-obese controls. Knockdown of FKBP5 in human adipocytes reduced GLUT1 gene expression and insulin-stimulated AKT Ser473 phosphorylation, however, maximal insulin-stimulated glucose uptake rate remained unchanged. Our findings suggest that FKBP5 levels in adipose tissue are reduced in obesity, and this decrease impairs insulin signaling in adipocytes without altering maximal glucose capacity, indicating a limited effect on glucose uptake under the tested conditions.

While obesity and type 2 diabetes (T2D) are associated with altered dopaminergic activity in the central nervous system and in adipose tissue (AT), the directions and underlying mechanisms remain inconclusive. Therefore, we characterized changes in the abundance of dopamine, its metabolites, and receptors DRD1 and DRD2 in the brain and AT upon dietary intervention or obesity. Male Wistar rats were fed either a standard pellet diet, a cafeteria diet inducing obesity and insulin resistance, or a calorie-restricted diet for 12 weeks. Abundance of dopamine and its receptors DRD1 and DRD2 were examined in brain regions relevant for feeding behavior and energy homeostasis. Furthermore, DRD1 and DRD2 protein levels were analyzed in rat inguinal and epidydimal AT and in human subcutaneous and omental AT from individuals with or without obesity. Rats with diet-induced obesity displayed higher dopamine levels, as well as DRD1 or DRD2 receptor levels in the caudate putamen and the nucleus accumbens core. Surprisingly, caloric restriction induced similar changes in DRD1 and DRD2, but not in dopamine levels, in the brain. Both diets reduced DRD1 abundance in inguinal and epidydimal AT, but upregulated DRD2 levels in inguinal AT. Furthermore, in human obesity, DRD1 protein levels were elevated only in omental AT, while DRD2 was upregulated in both omental and subcutaneous AT. These findings highlight dopaminergic responses to changes in energy balance, occurring both in the brain and AT. We propose that dopaminergic pathways are involved in tissue crosstalk during the development of obesity and T2D.

Context

Obesity and insulin resistance in men are linked to decreased testosterone and increased estradiol (E2) levels. Aromatase (ARO) converts testosterone into E2, and this occurs mainly in adipose tissue in men. E2 acts through estrogen receptors ESR1 and ESR2, and they potentially affect development of type 2 diabetes (T2D).

Objective

This study explored alterations in ARO, ESR1, and ESR2 in men with obesity or T2D.

Methods

Subcutaneous adipose tissue (SAT) from men with or without obesity or T2D was analyzed for ARO, ESR1, and ESR2 gene and protein expression. Data were compared across groups and correlated with markers of obesity, glycemia, insulin resistance, and sex hormones. Moreover, SAT was incubated with E2 or testosterone for ex vivo glucose uptake measurements.

Results

ARO levels were higher in SAT from men with obesity compared to nonobese men, and gene expression correlated positively with adiposity, hyperglycemia, and insulin resistance. No association was found between ARO and circulating E2. Men with obesity had lower levels of ESR1 and ESR1:ESR2 ratio, but not ESR2. ESR1 gene expression in SAT correlated negatively with adiposity and insulin resistance markers as well as with ARO expression, and tended to be lower in men with T2D. E2 reduced insulin-stimulated glucose uptake, while testosterone increased basal glucose uptake in adipocytes.

Conclusion

Elevated ARO in SAT was found in obese men, and this was linked to insulin resistance and glycemia, supporting the idea that local estrogen production contributes to metabolic dysregulation. ESR1 was reduced in men with T2D and was linked to adiposity and insulin resistance. Taken together, high ARO and altered ESR1:ESR2 balance in SAT in obese men may contribute to insulin resistance and T2D development.

This study aimed to evaluate the effects of a cafeteria diet and caloric restriction on behavioral and metabolic profiles of adult male Wistar rats. The rats were randomly divided into three groups (n = 12/group) and from 10 weeks of age fed either ad libitum standard rat chow (control group), ad libitum cafeteria diet in addition to standard chow (diet-induced obesity (DIO) group) or kept on caloric restriction (at 85% weight of controls; restricted group) for a period of 12 weeks. Body weight was assessed twice per week and glucose levels were measured at three times during the 12-week period. At week 11 the animals were behaviorally profiled using the multivariate concentric square fieldTM (MCSF) test. After 12 weeks of diet the animals were euthanized, blood collected, relative organ weights were assessed and plasma or serum levels of insulin, glucose, and lipid profile were measured. The DIO group gained 23% more weight than the control group (p < 0.001) and increased adipose tissue weight in comparison to the control (p < 0.001) and restricted (p < 0.001) groups. Glucose was significantly increased (p < 0.001) only during the second measurement at week 7 and insulin levels were elevated in the DIO group compared to controls and restricted groups (p < 0.01; p < 0.001, respectively). Plasma cholesterol levels were reduced for both DIO (p < 0.01) and restricted (p < 0.001) groups relative to controls. Adiponectin and leptin levels were higher for the DIO group in comparison to both the control (p < 0.001; p < 0.05) and restricted (p < 0.001; p < 0.001) groups. Thus, the two diets led to significant changes in body weight gain, adiposity, and metabolism. However, they did not alter the behavioral profiles in the MCSF test, suggesting that activity, exploration, risk assessment, risk taking or shelter seeking remained unaffected by the dietary interventions. The current findings suggest that an increase or reduction in energy intake resulted in no behavioral effects, despite the accompanying glycemic alterations potentially related to diabetes development.

Background: Alterations in kidney-associated adipose tissue depots, specifically renal sinus (RSAT) and perirenal adipose tissue (PRAT), may contribute to metabolic, cardiovascular, and chronic kidney diseases. We compared transcriptomic profiles and phenotypes, including adipocyte size, glucose uptake, and insulin action in RSAT and PRAT from healthy individuals.

Methods: Subcutaneous (SAT), omental (OAT) and renal adipose tissue biopsies were collected from healthy kidney donors (20 women, 20 men; BMI 20 to 36 kg/m2). Adipocyte size and basal and insulin-stimulated glucose uptake rate were measured in isolated adipocytes. Transcriptomic profiling and immune cell composition estimates (RNA seq, n = 30), were performed to evaluate differences between PRAT and RSAT, with OAT as a benchmark.

Results: PRAT exhibited significantly larger adipocytes and higher insulin-stimulated glucose uptake than RSAT. Of 1113 significantly differentially expressed genes (DEGs) (PRAT: 571 down- and 542 upregulated), thermogenic and metabolic genes (UCP1, CIDEA, and CKMT1B) were enriched in PRAT, while inflammation-related genes (NFKBIA, BIRC3, and IRF1) in RSAT. Pathway analysis indicated activation of metabolic pathways (TCA cycle and oxidative phosphorylation), in PRAT, which contrasts with the immune and inflammatory pathways in RSAT and OAT. Immune cell gene signatures revealed an anti-inflammatory environment in PRAT (eosinophils and activated NK cells), and a pro-inflammatory profile in RSAT (M0 macrophages). Immunohistochemistry confirmed higher CD68- and IL1B-positive cells in RSAT than in PRAT. When overweight individuals were compared to lean, genes related to the VEGF signaling were upregulated in PRAT and Ras signaling in RSAT. Additionally, metabolic pathways linked to the TCA cycle as well as carbon and fatty acid metabolism were downregulated.

Conclusions: The different kidney-associated adipose tissue depots exhibit distinct gene expression and functional profiles. PRAT displays higher expression of thermogenic markers and less inflammatory profile compared to RSAT and also OAT. In contrast, RSAT exhibits an inflammatory and macrophage-enriched profile, more closely resembling OAT. This study highlights the heterogeneity of the kidney-associated adipose tissue depots and could suggest that an excessive amount of RSAT may impact development of metabolic, cardiovascular, and chronic kidney diseases.

Purpose: Obesity is associated with neuroendocrine and metabolic dysregulation, yet the underlying mechanisms remain incompletely understood. This study aimed to investigate how pituitary hormonal axes and peripheral hormones respond to a cafeteria diet or a calorie-restricted diet in rats.

Methods: Ten-week-old male Wistar rats (n = 36) were randomized (1:1:1) to one of three diets for 12 weeks: an ad libitum standard rat chow diet (control group); an ad libitum cafeteria diet, containing cheese doodles, chocolate balls and salted peanuts, in addition to standard chow (diet-induced obesity group, DIO); or calorie-restriction (aiming at 85% body weight of controls; restricted group). We assessed endocrine gland weights, plasma levels of pituitary hormones and related peripheral signals, and explored their associations with metabolic and behavioral outcomes.

Results: While the DIO group exhibited increased body weight, insulin resistance, and altered metabolic markers, only modest changes in pituitary hormones were observed, with a reduction in luteinizing hormone (p < 0.05). Correlation analysis showed that when combining the control and DIO groups, prolactin inversely correlated with exploratory-activity (rho =-0.458, p < 0.05) from the behavioral test. In contrast, the restricted group showed more pronounced hormonal changes, including reduced levels of adrenocorticotropic hormone (p < 0.01), prolactin, and thyroid-stimulating hormone (both p < 0.05) as well as insulin-like growth factor-1 (p < 0.01). Multivariate data analysis showed a clear separation of the DIO group from the other groups, mainly driven by metabolic variables.

Conclusion: Despite notable metabolic perturbations in the DIO group, the absence of endocrine changes suggests a partly different phenotype than what is typically observed in humans with obesity.

Aims:

In addition to weight loss, obesity surgery (OS) leads to metabolic improvements that seem at least partly independent of weight loss and are also mediated by various endocrine pathways and the brain. For the first time, we compared the short-term effects of weight loss achieved by either OS or a low-energy diet (LED) on several hormonal systems, at fasting and upon an oral glucose challenge.

Materials and Methods:

This study presents sub-analyses from a randomized controlled trial including 24 participants with obesity but without diabetes (BMI 35-45 kg/m(2)), randomized 2:1 to either OS or 4-week LED leading to comparable weight loss. Circulating levels of gut, pituitary, adrenal, thyroid hormones, glucagon, insulin-like growth factor-1 and sex hormone-binding globulin were measured at baseline and 4 weeks after either intervention, both at fasting and during an oral glucose tolerance test (OGTT).

Results:

At 4 weeks, similar weight loss was achieved for the two interventions (7.7 for OS vs. 7.4% for LED). glucagon-like peptide-1 and peptide YY secretion during the OGTT increased after OS (p < 0.001 for OGTT(AUC) for both hormones), but not LED, while glucagon secretion remained unaffected. Adrenocorticotropin, cortisol and prolactin levels during OGTT were increased after OS (p = 0.04, p < 0.001, p = 0.002, respectively), while parathyroid hormone levels were decreased (p = 0.007). Fasting triiodothyronine levels were reduced after OS (p = 0.01). Fasting sex hormone-binding globulin levels decreased after both interventions (p < 0.01).

Conclusion:

Rapid and extensive hormonal changes occur after OS, but not LED, despite similar weight loss. Of note, few differences were seen in the fasting state, whereas multiple endocrine pathways were affected during the oral glucose challenge. The findings suggest altered responses to oral glucose after OS in several hypothalamus-pituitary endocrine axes and peripheral endocrine glands.

Aims: In addition to weight loss, obesity surgery (OS) leads to metabolic improvements that seem at least partly independent of weight loss and are also mediated by various endocrine pathways and the brain. For the first time, we compared the short-term effects of weight loss achieved by either OS or a low-energy diet (LED) on several hormonal systems, at fasting and upon an oral glucose challenge.

Materials and Methods: This study presents sub-analyses from a randomized controlled trial including 24 participants with obesity but without diabetes (BMI 35-45 kg/m(2)), randomized 2:1 to either OS or 4-week LED leading to comparable weight loss. Circulating levels of gut, pituitary, adrenal, thyroid hormones, glucagon, insulin-like growth factor-1 and sex hormone-binding globulin were measured at baseline and 4 weeks after either intervention, both at fasting and during an oral glucose tolerance test (OGTT).

Results: At 4 weeks, similar weight loss was achieved for the two interventions (7.7 for OS vs. 7.4% for LED). glucagon-like peptide-1 and peptide YY secretion during the OGTT increased after OS (p < 0.001 for OGTT(AUC) for both hormones), but not LED, while glucagon secretion remained unaffected. Adrenocorticotropin, cortisol and prolactin levels during OGTT were increased after OS (p = 0.04, p < 0.001, p = 0.002, respectively), while parathyroid hormone levels were decreased (p = 0.007). Fasting triiodothyronine levels were reduced after OS (p = 0.01). Fasting sex hormone-binding globulin levels decreased after both interventions (p < 0.01).

Conclusion: Rapid and extensive hormonal changes occur after OS, but not LED, despite similar weight loss. Of note, few differences were seen in the fasting state, whereas multiple endocrine pathways were affected during the oral glucose challenge. The findings suggest altered responses to oral glucose after OS in several hypothalamus-pituitary endocrine axes and peripheral endocrine glands.

Objective: Previous research points to a role of the brain in the regulation of glucose and pathogenesis of type 2 diabetes (T2D) via modulation of counter-regulatory hormone secretion and activity in the autonomic nervous system (ANS). The aim of this study was to investigate glucose-dependent responses of catecholamines and ANS activity in individuals with T2D, prediabetes (PD), and normoglycemia (NG). Design: Cross-sectional.

Methods: Individuals with T2D (n = 19, 7 men, HbA1c 49 mmol/mol), PD (n = 18, 8 men), and NG (n = 17, 3 men) underwent 1 stepwise hyperinsulinemic-euglycemic-hypoglycemic and 1 hyperglycemic clamp with repeated measurements of catecholamines, symptoms, heart rate variability (HRV), and hemodynamics.

Results: The hypoglycemic response of adrenaline was augmented in T2D and PD vs NG (both P < .05), and there was a strong association with insulin resistance (P < .05 for M-value). In relation to achieved glucose levels in both clamps, noradrenaline exhibited a steeper rise during hypoglycemia in T2D vs NG and PD (both P < .05). There were trends toward more marked autonomic hypoglycemic symptoms in T2D vs PD and NG. By contrast, insulin resistance was associated with attenuated responses of heart rate and HRV indices P-LF and P-HF at the target glucose plateau of 2.7 mmol/L (P < .05), independent of BMI and HbA1c.

Conclusion: Alterations in glucose-dependent responses of counter-regulatory hormones and the ANS appear before, and probably contribute to, the onset of T2D. Together with other reported alterations in neuroendocrine pathways, the findings suggest that a maladaptation of the brain's responses to glucose fluctuations is important in T2D progression.

Context Insulin-antagonistic, counter-regulatory hormones have been implicated in the development of type 2 diabetes (T2D).Objective In this cross-sectional study, we investigated whether glucose-dependent regulation of such hormones differ in individuals with T2D, prediabetes (PD), and normoglycemia (NG).Methods Fifty-four individuals with or without T2D underwent one hyperinsulinemic-normoglycemic-hypoglycemic and one hyperglycemic clamp with repeated hormonal measurements. Participants with T2D (n = 19) were compared with a group-matched (age, sex, BMI) subset of participants without diabetes (ND, n = 17), and also with participants with PD (n = 18) and NG (n = 17).Results In T2D vs ND, glucagon levels were higher and less suppressed during the hyperglycemic clamp whereas growth hormone (GH) levels were lower during hypoglycemia (P < .05). Augmented ACTH response to hypoglycemia was present in PD vs NG (P < .05), with no further elevation in T2D. In contrast, glucagon and GH alterations were more marked in T2D vs PD (P < .05). In the full cohort (n = 54), augmented responses of glucagon, cortisol, and ACTH and attenuated responses of GH correlated with adiposity, dysglycemia, and insulin resistance. In multilinear regressions, insulin resistance was the strongest predictor of elevated hypoglycemic responses of glucagon, cortisol, and ACTH. Conversely, fasting glucose and HbA1c were the strongest predictors of low GH levels during hypoglycemia and elevated, i.e. less suppressed glucagon levels during hyperglycemia, respectively. Notably, adiposity measures were also strongly associated with the responses above.Conclusions Altered counter-regulatory hormonal responses to glucose variations are observed at different stages of T2D development and may contribute to its progression by promoting insulin resistance and dysglycemia.