Endocrinology最新文献

Estrogens have considerable effects on energy homeostasis and metabolic health. In mice, signaling through estrogen receptor α (ERα) alters energy intake and expenditure, effects that may be mediated by specific regions or cellular subpopulations of the hypothalamus. This study investigates the function of ERα signaling in the lineage that expresses Rprm (reprimo), a gene we previously linked to thermoregulation in females. Here, we engineered a novel ReprimoCre mouse to selectively knock out ERα in Rprm lineage cells (Reprimo-specific ERα knockout [KO]; RERKO). We report modest changes in core temperature, higher brown adipose tissue (BAT) mass, elevated BAT temperature during the light phase, and lower tail temperature during the light phase in RERKO females relative to controls. RERKO females also exhibited a subtle difference in locomotion and no differences in feeding or body mass. These phenotypes suggest sex-specific effects on the patterns of body temperature instead of overall increases or decreases in heat generation or dissipation. Labeling of the Rprm lineage was detected in the brain, but not in BAT or white adipose, suggesting that temperature changes may be mediated by the nervous system. To test for centrally mediated effects on temperature, we ablated Rprm-expressing cells in the mediobasal hypothalamus. Although this approach eliminates the cells entirely instead of selectively eliminating ERα in Rprm-expressing cells, we observed a phenotype similar to RERKO mice, with effects on core temperature and BAT mass. Together, these results indicate that estrogen signaling in the Rprm lineage is important for thermoregulation in female, but not male, mice.

LH/choriogonadotropin (hCG) receptor (LHCGR) and the G protein-coupled estrogen receptor (GPER) are coexpressed in the ovary and support reproduction. The latter is involved in pathophysiological conditions and has been suggested as a potential therapeutic target. However, its role is still controversial, and several studies reported GPER to form heterocomplexes with other class A G protein-coupled receptors, modulating their signaling cascades. We evaluated if GPER interacts with LHCGR and impacts ligand-mediated pathways. In HEK293, LHCGR-GPER heteromers allosterically modulate LH/hCG-mediated signaling by preventing receptor coupling with Gq protein, leading to inhibition of phospholipase C pathway, and related transcriptional and mitogenic functions. This effect is prevented by mutant GPER unable to form heteromers with LHCGR. Interestingly, GPER expression has no effect on LH/hCG-induced Gs/cAMP/protein kinase A pathway activation, demonstrating selective inhibition of Gq pathway. These results were not recapitulated in cells displaying insufficient endogenous Gq protein expression levels, whereas they are recovered under exogenous Gq overexpression. Our data strengthen the concept that GPER may act as a modulator of other membrane G protein-coupled receptors, and a potential new target for treatment of tumors displaying Gq signalling.

17β-hydroxysteroid dehydrogenase 1 (HSD17B1) is the primary enzyme responsible for the activation of estrone (E1) to estradiol (E2) in ovaries and extra-gonadal tissues of both humans and rodents. In the present study, molecular modeling identified the substitution of His222 in the human HSD17B1 enzyme with glycine in the mouse as the key determinant for the different steroid specificity between the species. Furthermore, Ser143Ala mutation at the active site of mouse HSD17B1 resulted in a total loss of E1 to E2 conversion by HSD17B1. This resulted in elevated intraovarian and circulating E1 concentrations in adult HSD17B1 Ser143Ala knock-in (HSD17B1-KI) females, but no changes in E2 concentrations were observed compared to the wild-type mice. Androstenedione and dihydrotestosterone were also elevated in the HSD17B1-KI ovaries, associated with elevated circulating LH. However, the effect of HSD17B1 inactivation on female reproductive development and function was mild, primarily resulting in a slight decrease in ovarian weight in older HSD17B1-KI mice, without notable effects on fertility. Expression of genes related to steroid biosynthesis, mitochondrial metabolism, and known markers of polycystic ovary syndrome was found to be upregulated in adult HSD17B1-KI ovaries. However, no alterations in the structure or function of extra-gonadal tissues were observed, and the uterus and bone phenotypes in the HSD17B1-KI females were unaffected. Our results demonstrate that the blockade of HSD17B1-dependent E2 synthesis is successfully compensated for in mouse in vivo, resulting in only a mild ovarian estrogen and androgen imbalance but no significant adverse effects on reproductive or bone health.

Polycystic ovary syndrome (PCOS) is associated with a high prevalence of insulin resistance (IR) and obesity. Adiponectin, an insulin-sensitizing hormone, is reduced in PCOS and inversely correlated with IR and obesity. This study tested whether androgens reduce adiponectin, and if the adiponectin receptor agonist AdipoRon improves IR and obesity in a PCOS model. Four-week-old female Sprague Dawley rats were implanted with dihydrotestosterone (DHT) or control Silastic tubes for 12 weeks. After 6 weeks of DHT treatment, rats received AdipoRon or vehicle in their food for 6 weeks. DHT increased body weight, fat and lean mass, food intake, serum leptin, adipose mitochondrial oxidative stress, inflammatory markers, HOMA-IR, adipocyte size, and decreased serum adiponectin levels. DHT upregulated GLUT4, PPARγ, and adiponectin mRNA expression in subcutaneous adipose tissue (SAT), while PPARγ was downregulated in visceral adipose tissue (VAT). DHT also reduced Akt protein expression in SAT and p(S473)-Akt phosphorylation in VAT and caused a depot-specific effect on androgen receptor expression. AdipoRon reduced body weight, fat, and lean mass, food intake, serum leptin, adipocyte size, and IR markers in DHT-treated rats. AdipoRon upregulated Akt, AMPK, and AdipoR1 mRNA expression in SAT and increased p(S473)-Akt phosphorylation in both white adipose tissue (WAT) depots. AdipoRon also reduced mitochondrial oxidative stress in both WAT depots and decreased androgen receptor expression in VAT. AdipoRon attenuates hyperandrogenemia-induced adiposity and IR in a PCOS model by improving adipose insulin and adiponectin signaling, reducing mitochondrial oxidative stress and food intake, supporting its therapeutic potential in managing IR and obesity in PCOS women.

Background: The global obesity epidemic necessitates the identification of novel therapeutic targets. Although central administration of α-Klotho improves metabolic function in rodents, its precise mechanisms of action remain unclear. Since α-Klotho signals through fibroblast growth factor receptors (FGFRs), we hypothesized that FGFR1 within specific hypothalamic neuronal populations is critical for maintaining metabolic homeostasis.

Methods: We investigated the metabolic role of FGFR1 in the arcuate nucleus of adult mice using an adeno-associated virus (AAV)-mediated CRISPR/Cas9 system, in conjunction with transgenic models, to achieve cell-type-specific knockout of FGFR1 in mature glutamatergic, gamma-aminobutyric acid (GABA)ergic, and agouti-related peptide (AgRP) neurons.

Results: We found that FGFR1 governs distinct metabolic functions in different neuronal populations. Conditional deletion of FGFR1 in glutamatergic neurons impaired glucose tolerance. In contrast, its ablation in GABAergic neurons induced a severe energy imbalance, resulting in obesity characterized by significant weight gain and adiposity. Notably, AgRP neuron-specific deletion of FGFR1 recapitulated this obese phenotype. Furthermore, the loss of FGFR1 in AgRP neurons disrupted α-Klotho signaling, preventing its ability to modulate AgRP neuron activity and abolishing its beneficial effects on glucose and energy metabolism.

Conclusion: Our results establish FGFR1 in hypothalamic neurons as an essential component of the pathway through which α-Klotho regulates systemic energy balance. These findings identify hypothalamic FGFR1 as a critical molecular target for developing anti-obesity therapies.

Blood-brain barrier (BBB) breakdown plays a key role in cognitive impairment in diabetic encephalopathy (DE). This study aimed to investigate whether myeloid-derived growth factor (MYDGF) can prevent BBB injury and cognitive impairment in DE. Circulating MYDGF levels were measured in patients with diabetes. In vivo experiments, both loss- and gain-of-function strategies, were used to evaluate the effect of MYDGF on BBB injury and cognitive impairment in diabetic mice. We used multiple low-dose streptozotocin-treated Mydgf knockout and wild-type (WT) mice on high-fat diets to induce diabetes. Then, cognitive function and BBB permeability were examined in diabetic mice that were subjected to adeno-associated virus-mediated Mydgf gene transfer. In vitro experiments, primary human brain microvascular endothelial cells (HBMECs) were treated with high glucose (HG) to mimic diabetic conditions. The effects of MYDGF on transendothelial permeability were investigated. The results indicated that circulating MYDGF levels were decreased in patients with DE and diabetic mice with cognitive impairment. Compared with WT mice, MYDGF deficiency presented more severe impaired cognitive performance, BBB leakage, and cerebrovascular inflammation in diabetic mice. Inversely, MYDGF restoration alleviated cognitive decline, BBB breakdown, and cerebrovascular inflammation in diabetic mice. In HG-treated HBMECs, MYDGF restoration attenuated the transendothelial permeability and junction protein downregulation and protected against endothelial inflammation and apoptosis. Mechanistically, the protective effect of MYDGF was attributed to mitogen-activated protein kinase kinase kinase kinase 4/nuclear factor-kappa B signaling pathway inhibition. This study demonstrated that MYDGF protects against BBB injury and prevents the progression of cognitive decline in DE, suggesting that MYDGF may be an effective therapeutic strategy for DE.

Aromatase inhibitors (AI) are first-line therapy for postmenopausal women with estrogen receptor-expressing (ER+) breast cancer (BC). AI therapy effectively reduces recurrence and extends lifespan for patients with ER+ BC through long-term estrogen deprivation (LTED) resulting from inhibition of the enzyme aromatase that converts androgens to estrogens. However, up to 50% of ER+ BC recurs as AI-resistant metastatic disease within 10 years of diagnosis. AI-resistant BC upregulates androgen receptors (AR) and mitochondrial oxidative phosphorylation (OXPHOS) and requires OXPHOS and fatty acid oxidation (FAO). The liver and lung, common ER+ BC metastatic sites, have high abundance of the saturated fatty acid palmitate. We asked whether AR signaling regulates OXPHOS in the context of LTED. Using mutant ER-expressing MCF7 and T47D BC cell lines with AR antagonism via the anti-androgen enzalutamide and with shRNA knockdown, we demonstrate that AR supports cell growth, OXPHOS, FAO, and resistance to palmitate lipotoxicity. We identify AR as a positive regulator of the carnitine acyltransferase family enzyme CRAT that promotes OXPHOS capacity. These studies identify AR as pro-tumor in the LTED setting and as a therapeutic target for ER-mutant BC that develops under the selective pressure of AI therapy.