| 1. |
- Ahmed, Fozia
(författare)
-
Estrogen and its receptors in adipose tissue from women and men : Associations with age, adiposity and type 2 diabetes
- 2024
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity and its complications, such as insulin resistance and type 2 diabetes (T2D), are leading causes of morbidity and mortality globally. Adipose tissue is important for whole-body homeostasis, functioning as an energy storage reservoir and an endocrine organ. Estrogens mediate their effects through estrogen receptor alpha (ESR1) and beta (ESR2) and contribute to sex and menopause-related differences in body fat distribution. Moreover, estrogens can be produced from androgens in the adipose tissue by the enzyme aromatase. The overall aim of this thesis was to investigate the role of estrogen and estrogen signalling in human adipose tissue and their association with age, adiposity, and insulin resistance. In Paper I, we assessed ESR1 and ESR2 gene expression in subcutaneous adipose tissue (SAT) from pre- and postmenopausal women, and investigated the effects of estradiol on adipocyte glucose uptake. We found that ESR2 gene expression was higher in postmenopausal women than premenopausal women. Moreover, in late, but not pre- or early postmenopausal women, estradiol incubation reduced basal and insulin-stimulated glucose uptake, which corresponded to an increase in ESR2 gene expression levels. The inhibiting effect of estradiol on adipocyte glucose uptake was prevented using an ESR2 antagonist. Subsequently, in Paper II we assessed the role of ESR2 in SAT lipid and glucose metabolism and preadipocyte differentiation. ESR2 expression in SAT was inversely correlated with markers of central adiposity and positively correlated with markers of lipid accumulation. Moreover, ESR2 knockdown impaired subcutaneous preadipocyte differentiation and glucose utilization. In Paper III, we focused on adipocyte lipolysis in women, which is regulated, in part, by catecholamines. OCT3, which mediates catecholamine transport into adipocytes, where they can be degraded, was increased in SAT with age, and higher in postmenopausal women than premenopausal women. Moreover, its expression was negatively associated with markers of insulin resistance and ex vivo lipolysis. Estradiol incubation of SAT downregulated OCT3 gene expression, which may explain lower OCT3 gene expression in premenopausal compared to postmenopausal women. In Paper IV, we focused on the role of aromatase and estradiol in SAT from men. We found that aromatase expression was higher in SAT from men with obesity and T2D compared to subjects without obesity and T2D, respectively, and was positively associated with markers of central obesity and markers of insulin resistance. Contrastingly, ESR1 expression in SAT was lower in men with obesity and T2D compared to subjects without obesity and T2D, respectively, and negatively associated with markers of obesity and insulin resistance. ESR2 expression was higher in SAT from men with T2D compared to men without T2D. Estradiol reduced insulin-stimulated glucose uptake, however, neither testosterone, nor aromatase inhibition, altered adipocyte glucose uptake. In this thesis, we found that estrogen has important metabolic effects in adipose tissue, including regulating lipid accumulation, glucose uptake capacity, and catecholamine transport. Overall, our findings suggest that estrogen and estrogen receptors may have an important role in age-, menopausal- and sex-dependent differences in body fat distribution, and may serve as potential targets for the prevention and treatment obesity and insulin resistance.
|
|
| 2. |
- Lundqvist, Martin H., et al.
(författare)
-
Regulation of the Cortisol Axis, Glucagon, and Growth Hormone by Glucose Is Altered in Prediabetes and Type 2 Diabetes
- 2024
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Endocrine Society. - 0021-972X .- 1945-7197. ; 109:2, s. e675-e688
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 3. |
- Vranic, Milica, et al.
(författare)
-
Subcutaneous adipose tissue dopamine D2 receptor expression is increased in prediabetes and T2D
- 2024
-
Ingår i: Endocrine. - : Springer. - 1355-008X .- 1559-0100. ; 83
-
Tidskriftsartikel (refereegranskat)abstract
- PurposeTo evaluate the dopaminergic signaling in human adipose tissue in the context of obesity and type 2 diabetes (T2D) and potential direct implications in adipose tissue metabolism.MethodsmRNA and protein expression of dopamine receptors D1 and D2 (DRD1 and DRD2) were determined in subcutaneous adipose tissue from subjects without or with T2D and with different body weight, and correlated with markers of obesity, hyperglycemia, and insulin resistance. Glucose uptake and lipolysis were measured in adipocytes ex vivo following short-term exposure to dopamine, DRD1 receptor agonist (SKF81297), or DRD2 receptor agonist (bromocriptine).ResultsDRD1 and DRD2 gene expression in subcutaneous adipose tissue correlated positively with clinical markers of insulin resistance (e.g. HOMA-IR, insulin, and triglycerides) and central obesity in subjects without T2D. Protein expression of DRD2 in subcutaneous adipose tissue, but not DRD1, is higher in subjects with impaired fasting glucose and T2D and correlated positively with hyperglycemia, HbA1c, and glucose AUC, independent of obesity status. DRD1 and DRD2 proteins were mainly expressed in adipocytes, compared to stromal vascular cells. Dopamine and dopaminergic agonists did not affect adipocyte glucose uptake ex vivo, but DRD1 and DRD2 agonist treatment inhibited isoproterenol-stimulated lipolysis.ConclusionThe results suggest that protein expression of DRD2 in subcutaneous adipose tissue is up-regulated with hyperglycemia and T2D. Whether DRD2 protein levels contribute to T2D development or occur as a secondary compensatory mechanism needs further investigation. Additionally, dopamine receptor agonists inhibit adipocyte beta-adrenergic stimulation of lipolysis, which might contribute to the beneficial effects in lipid metabolism as observed in patients taking bromocriptine.
|
|
