American journal of physiology. Endocrinology and metabolism最新文献

FGF21 is a hormone secreted from the liver in response to various nutritional stressors, suggested to act to balance dietary intake through negative feedback regulation. This meal study aimed to investigate two different potential nutrient interactions on postprandial FGF21 secretion in healthy human participants: 1) between intake of alcohol and protein, and 2) between intake of alcohol and vitamin A (retinol). In a 4-arm, randomized, double-blinded, cross-over meal study (NCT06105476), postprandial circulating concentrations of FGF21, glucose, insulin, ethanol, and acetate were compared after intake of four different test drinks containing alcohol, alcohol + protein, alcohol + retinol, or retinol in 27 healthy humans. The postprandial FGF21 response to the alcohol + protein drink was severely attenuated compared with the alcohol drink. The FGF21 response to the alcohol + retinol drink was similar to the alcohol drink, whereas there was no FGF21 response to the drink with retinol only. In conclusion, intake of protein inhibited the secretory FGF21 response to alcohol intake, whereas retinol intake did not appear to influence FGF21 secretion.NEW & NOTEWORTHY The hepatic hormone FGF21 is regulated by dietary intake. The results of this human meal study suggest that coconsumption of protein inhibits alcohol-induced FGF21 secretion in humans, similar to how protein intake previously has been shown to inhibit sugar-induced FGF21 secretion. This indicates that dietary protein is a consistent downregulator of FGF21. We found no indication that intake of retinol influences FGF21 regulation.

Bile acids (BAs) act as hormonal ligands of the hepatic and intestinal receptor farnesoid X receptor and stimulators of fibroblast growth factor 19 (FGF-19) and glucagon-like peptide-1 (GLP-1) secretion. Although metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to BAs dysregulation, the effects of advanced fibrosis on plasma and fecal BAs profiles remain unclear. We compared 35 plasmatic and fecal BAs concentrations and qualitative pools, including primary, secondary, unconjugated, and conjugated BAs in the fasting state between individuals with advanced fibrosis stages (F3-F4/4) (n = 28) and individuals without advanced fibrosis (n = 26). Median age (interquartile range (IQR)) (56 [48-65] vs. 57 [49-66] yr), sex (62 vs. 60% man), and body mass index (32 [29-36] vs. 34 [32-38] kg/m²) were comparable between groups. Total plasmatic BAs concentration was increased in the advanced stage of fibrosis (P < 0.01), whereas total stool BAs concentration did not differ between groups (P = 0.36). Participants with advanced fibrosis had higher chenodeoxycholic acid family BAs, which were driven by increased glyco- and tauro-conjugated forms (P < 0.05). Plasma unconjugated secondary BA lithocholic acid was also higher in advanced fibrosis (P < 0.01), but we did not find a change in intestinal microbiota bile salt hydrolase enzymatic activity, which is responsible for the deconjugation of BAs. There were no differences in FGF-19 and GLP-1 concentrations between groups. Overall, our results lead us to hypothesize that the increase in hepatic bile acid production in cases of MASLD with advanced fibrosis may occur mainly via the acid pathway or leakage of BAs from the liver into the plasma caused by hepatic inflammation, without changes in intestinal BAs metabolism. This profile of increased hydrophobic plasma BAs may contribute to MASLD progression, inflammation, and oxidative stress.NEW & NOTEWORTHY This study explored detailed plasma and fecal concentrations of 35 bile acids in MASLD with advanced fibrosis. Total, primary, and secondary plasmatic bile acids, particularly the CDCA family, were increased in advanced fibrosis without changes in their effectors, FGF-19/GLP-1. This profile may lead to a proinflammatory BA profile. We also showed that novel, unstudied BAs species are of interest in advanced fibrosis, such as glucuronides.

Type 2 diabetes is considered the pandemic of the 21st century. The pathogenesis of diabetes is complex and multifactorial, and its understanding is crucial for its prevention and treatment. Nevertheless, the pathogenesis of β-cell dysfunction remains unclear. This gap in knowledge could be related to a lack of appropriate preclinical models of type 2 diabetes. Current animal models, mostly genotypic and monogenic, do not fully reflect the pathophysiology of type 2 diabetes or associated organ damage. Therefore, a new preclinical model is needed. In this study, we present a non-genotypic animal model of diabetes that combines obesity and the treatment with the diabetogenic immunosuppressor tacrolimus (TAC). Sprague-Dawley male rats were fed with a high-fat diet (HF) to establish obesity and metabolic syndrome. Then, TAC was administered for 6-9 mo to induce chronic hyperglycemia. These animals showed a decrease in Langerhans islets area and number, and development of islet fibrosis. There were also changes in pancreatic insulin and glucagon content, imbalance in the α/β-cell ratio and decrease in the expression of essential transcription factors V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA), forkhead box protein O1 A (FOXO1A), pancreatic and duodenal homeobox 1 (PDX-1), and neuronal differentiation 1 (NEUROD1). Altogether, this could be a more appropriate animal model to study the pathophysiology of diabetes and, eventually, related organ damage.NEW & NOTEWORTHY After 6-9 mo of treatment, animals presented fasting and chronic hyperglycemia in intraperitoneal glucose tolerance test (IPGTT). Pancreas of obese-diabetic animals showed a decrease in Langerhans islets area and number, and development of islet fibrosis. Islets showed a decrease in insulin content and in β-cells proportion, and an increase in α cells proportion. There was also a decrease in the expression of transcriptional factors essential for β cells: V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA), Forkhead box protein O1 A (FOXO1A), pancreatic and duodenal homeobox 1 (PDX-1), and Neuronal differentiation 1 (NEUROD1).

A carbohydrate-rich breakfast is commonly consumed by cyclists to compensate for an overnight decline in liver glycogen content and, as such, to maximize liver glycogen stores in the hours before exercise. However, the extent to which liver glycogen content increases in response to the intake of a carbohydrate-rich breakfast in well-trained cyclists remains unexplored. Twelve well-trained male cyclists (age: 25 ± 5 yr; V̇o_2peak: 67 ± 5 mL·min^-1·kg^-1; W_max: 5.8 ± 0.7 W·kg^-1) participated in this trial. Carbon-13 magnetic resonance spectroscopy (¹³C-MRS) at 7 T and magnetic resonance imaging (MRI) at 3 T were applied to assess muscle and liver glycogen concentrations and volume, respectively, before and 3 h after ingesting a carbohydrate-rich breakfast providing 3 g carbohydrates per kg body mass. Following breakfast ingestion, muscle glycogen concentrations, muscle volumes, and total muscle glycogen content did not change (P > 0.05). Liver glycogen concentrations increased by ∼10% (from 164 ± 30 to 180 ± 33 mmol/L; P = 0.036), whereas liver volumes decreased by ∼6% (from 1.96 ± 0.28 to 1.84 ± 0.27 L; P < 0.001) in the 3 h following breakfast ingestion. Consequently, no net change in overall liver glycogen content was observed following breakfast ingestion (from 53 ± 15 to 54 ± 13 g; P = 0.516). Ingesting a carbohydrate-rich breakfast (providing 3 g carbohydrates per kg body mass) does not elevate liver or muscle glycogen content during the subsequent 3-h postprandial period.NEW & NOTEWORTHY This is the first study to simultaneously assess both muscle and liver glycogen content following ingestion of a practical carbohydrate-rich breakfast in well-trained cyclists. No changes were observed in muscle glycogen concentrations or content. Liver glycogen concentrations increased postprandially, but liver glycogen content remained unchanged due to a concurrent decline in liver volume. These findings highlight the importance of accounting for liver volume changes when interpreting postprandial liver glycogen storage responses.

Immune checkpoint inhibitor PD-1 antibody (PD-1-Ab) has arisen the increasing clinical prevalence of immune-related adverse events (irAEs) such as hypothyroidism. Hypothyroidism is the common irAEs, but the mechanism of such immunological pathogenesis was still unclear. We have developed a unique hypothyroidism mice model induced by mimicking clinical exposure to PD-1-Ab. Then we analyzed the immune cell phenotypes in the peripheral blood of mouse models by flow cytometry and further verified in patients' samples. Therefore, we have further investigated the molecular pathogenesis of such condition through the spatial transcriptome sequencing in thyroid glands. Those findings have supported the recommendations of prophylactic treatment with thyroxine in a very beginning timepoint. The results showed that the CD4⁺T-cell subset declined in the peripheral blood of hypothyroidism mice induced by PD-1-Ab, which was consistent with the similarities in the patients with hypothyroidism. Moreover, spatial transcriptome sequencing of thyroid glands of mice was predominantly featured by upregulated IL-17 signaling pathway and involved endoplasmic reticulum stress, which provided the evidences to address the preliminary roles of immunological pathogenesis participated. In addition, we have demonstrated that a combination with early onset of thyroxine supplements could prevent the subsequent occurrence of hypothyroidism. Those experimental and clinical data provided the awareness that CD4⁺T cells are associated with hypothyroidism caused by PD-1-Ab, and therefore, prophylactic administration of thyroxine should be considered with great caution and in timely manner.NEW & NOTEWORTHY This study explored the immunopathogenic mechanism of immune checkpoint inhibitor associated hypothyroidism through T-cell phenotype and spatial transcriptome sequencing of thyroid glands of mimicked mice model. The findings revealed decreased CD4⁺T-cell subset and subsequently featured by upregulated IL-17 signaling pathway. The prophylactic thyroxine was recommended in the early onset of hypothyroidism.

This study investigates whether deviations in the regularity/complexity of urinary sex hormones relative to textbook "gold standard" (GS) menstrual cycle patterns are associated with vasomotor symptom (VMS) occurrence and how these relationships might relate to differences in hormonal profiles. A total of 549 midlife women provided daily urine-based measurements of follicle-stimulating hormone (FSH), estrogen conjugates (E1C), pregnanediol glucuronide (PDG), and luteinizing hormone (LH) over a complete menstrual cycle. Distribution and fuzzy entropy (DistEn and FuzzEn) were used to gauge hormone regularity/complexity, emphasizing structural complexity and temporal unpredictability, respectively. Entropy metrics were classified as being elevated or lowered relative to the GS and then evaluated in relation to VMS prevalence. These same entropy classifications were used to evaluate hormone profiles by referencing 11 dynamics indicative of normal or reproductively aging cycles. Elevated entropy was positively associated with the likelihood of VMS for PDG-DistEn and E1C-DistEn and negatively associated for PDG-FuzzEn, E1C-FuzzEn, and LH-FuzzEn. Lowered entropy was negatively associated with VMS likelihood for LH-FuzzEn and PDG-FuzzEn and positively associated for FSH-FuzzEn and E1C-DistEn. Entropy analysis provides useful insight into menstrual cycle dynamics and their associations with VMS. Specifically, entropy can identify different underlying states of hormonal dysregulation associated with increased VMS occurrence, potentially providing insights into VMS causes and treatments. Furthermore, entropy metrics for PDG show potential in gauging degrees of reproductive aging, which could help in addressing health risks associated with late/early menopause. Finally, entropy may contribute toward efforts in understanding how a woman's VMS experience will progress through the menopause transition.NEW & NOTEWORTHY There are a number of strong associations between the regularity/complexity of urinary sex hormones (being formalized via fuzzy and distribution entropy) and vasomotor symptoms (VMS). Standardized metrics of hormonal regularity (i.e., hormonal entropy) show promise in being used to identify different hormonal profiles underlying VMS occurrence, to provide a general gauge of reproductive aging, and to help predict the overall character of VMS experiences for the remainder of the menopause transition and beyond.

Glucagon-like peptide-1 (GLP-1) has previously been shown to be indispensable for optimal bone strength by acting at the bone material level. However, it was not fully clear whether the effects of GLP-1 were mediated by direct or indirect actions on bone cells. In the present study, we were unable to demonstrate the expression of the GLP-1 receptor (GLP-1r) in bone tissue at the gene expression level using qPCR and in situ hybridization, or at the protein level. Furthermore, the peripheral administration of exendin-4, a specific GLP-1r agonist, in ovariectomized BALB/c mice enhanced postyield displacement (18%) and energy-to-fracture (24%), as well as bone volume/total volume (BV/TV) (11%), trabecular number (Tb.N) (6%), and collagen maturity (18%). These bone effects were still observed when exendin-4 was centrally administered into the lateral cerebral ventricle. On the contrary, the peripheral administration of exendin-4 coupled to bovine serum albumin, a GLP-1r agonist that cannot penetrate the brain, failed to replicate the positive effects on bone despite increased calcitonin secretion. Altogether, these data confirm that GLP-1r agonists represent an interesting approach for managing bone fragility due to ovariectomy but also suggest that GLP-1r agonists require a central relay-yet to be identified-to exert positive effects on bone physiology. Further studies are needed to decipher the mechanisms of action of GLP-1 and GLP-1r agonists on bone physiology.NEW & NOTEWORTHY This study discovered that medications mimicking GLP-1, like exendin-4, improve bone strength and structure in mice, including better bone volume and collagen quality. Interestingly, exendin-4's effects were observed when delivered to the brain but not when prevented from reaching it. This suggests GLP-1 influences bones through brain signals rather than acting directly on bone. Although GLP-1 treatments show promise for preventing bone weakness, more research is needed to understand this brain-bone connection.

The circadian system coordinates 24-h cycles of internal biological processes with the environmental light-dark cycle. Abrupt shifts in the timing of the light-dark cycle misalign internal circadian clocks with the environment and cause jet lag until resynchronization occurs. The objective of this study was to investigate the sex difference in simulated jet lag in mice. Female mice resynchronized faster than male mice to 6-h advances of the light-dark cycle that mimicked eastward travel. Circulating estradiol was necessary and sufficient for rapid resynchronization in female mice since ovariectomized females resynchronized slower than mice treated with estradiol. Disabling estrogen receptor α (ERα), but not estrogen receptor β (ERβ) or G-protein-coupled estrogen receptor 1 (GPER1), abolished the sex difference in resynchronization. To investigate ERα-dependent mechanisms that regulate the rate of resynchronization, we measured the endogenous circadian period and the magnitudes of phase shifts to light pulses in male and female wild-type and ERα knockout mice. Wild-type females had shorter periods and greater phase delays in response to light pulses given in the early subjective night than male mice. Disabling ERα abolished these sex differences by lengthening the circadian period and reducing the magnitudes of phase delays. Together, these data suggest that ERα alters the rate of resynchronization to shifted light-dark cycles by regulating period length and phase shift magnitude in female mice. Understanding the mechanisms underlying the sex difference in resynchronization to shifted light-dark cycles can be used to develop strategies to alleviate jet lag and circadian misalignment.NEW & NOTEWORTHY Coordination of circadian rhythms with environmental cycles of light and dark is critical to well-being and healthspan. Jet lag is circadian misalignment that causes fatigue, insomnia, poor mood, impaired alertness, and gastrointestinal symptoms after travel across time zones. We show there is a sex difference in simulated jet lag in mice that is regulated by ERα signaling. Our findings reveal novel mechanisms that underlie jet lag to understand and develop interventions for circadian misalignment.

Acute exercise causes a short-term stress, activating immediate gene expression responses. These responses are essential for cellular adaptation and resilience. Endothelial cells, positioned throughout the vasculature, play a central role in sensing and responding to these stress signals. As dynamic regulators of vascular tone, nutrient delivery, and cellular communication, endothelial cells are key integrators of metabolic adaptation. They coordinate intra- and interorgan communication through the release of signaling molecules, shaping systemic responses to exercise. Despite their importance, the endothelial cell-specific transcriptional response to exercise remains poorly understood. To interrogate the transcriptional response to exercise in endothelial cells, we used NuTRAP (Nuclear Tagging and Translating Ribosome Affinity Purification) mouse technology that expresses EGFP/L10a under control of the vascular endothelial-cadherin promoter (NuTRAP^EC). Following a single bout of acute exercise, ribosome-associated mRNA was isolated from endothelial cells from gastrocnemius of both exercised and sedentary animals. RNA sequencing confirmed endothelial cell-specific enrichment and revealed robust changes in gene expression. Exercise induced canonical early response genes (Nr4a2, Sik1, and Slc25a25) and activated pathways related to angiogenesis, oxidative stress, stress kinase signaling, vascular remodeling, and metabolic stress signaling. For context, we analyzed skeletal muscle fiber responses using NuTRAP mice driven by the human α-skeletal actin (NuTRAP^SMF) mice. Although some genes overlapped, skeletal muscle fiber-enriched pathways included hypoxia response and muscle development. These findings reveal a distinct microvascular endothelial transcriptional signature in skeletal muscle tissue in response to acute exercise, providing insight into the cell-type-specific mechanisms that underlie vascular adaptation and intercellular communication in response to physiological stressors like exercise.NEW & NOTEWORTHY This study profiles the endothelial-specific transcriptional response to acute exercise at cell-type resolution. Comparative analysis with skeletal muscle fibers revealed distinct gene expression and upstream regulators. Key findings include endothelial-specific expression of exerkines, metabolic genes, and nitric oxide signaling. These results uncover a molecular basis for endothelial adaptation to exercise and suggest a potential role in mediating systemic exercise benefits.