American journal of physiology. Endocrinology and metabolism最新文献

β-Cell adaptation to maternal insulin resistance of pregnancy involves upregulation of β-cell mass and function, a process we previously showed depends on prolactin receptor (PRLR) signaling. Emerging evidence in humans suggests that prolactin signaling may also influence β-cell function beyond pregnancy. This study aims to investigate how postpregnancy metabolic stress-specifically the combined effects of prior pregnancy followed by high-fat diet (HFD) exposure-impacts β-cell function, with a focus on the role of PRLR. In this study, we found that multiparous transgenic female mice with β-cell-specific PRLR deletion (βPrlr^-/-) have impaired glucose tolerance when challenged with HFD. Unlike in pregnancy, where PRLR signaling upregulates β-cell proliferation and mass, we observed no difference in β-cell mass between the wild-type (βPrlr^+/+) and mutant (βPrlr^-/-) mice when metabolically stressed with HFD. However, βPrlr^-/- mice showed blunted first-phase insulin release in vivo when challenged with glucose orally but not intraperitoneally, suggesting an impaired incretin effect. Moreover, there is a reduction in the expression of incretin hormone receptor, Glp-1r, and several of its upstream regulators, such as E2f1, Nkx6.1, Pax6, Pparγ, and Tcf7l2. Interestingly, isolated islets from βPrlr^-/- mice showed intact in vitro glucose-stimulated insulin secretion (GSIS) but impaired incretin-potentiated GSIS. Islets from βPrlr^-/- mice also had a lower insulin content and expressed lower levels of genes that regulate glucose metabolism. Together, these results suggested that PRLR signaling plays an important role in preserving β-cell function in mice exposed to metabolic stress by maintaining incretin receptor expression and insulin secretory capacity in β-cells.NEW & NOTEWORTHY Prolactin receptor (PRLR) signaling is crucial for β-cell adaptation to metabolic stresses from repeated pregnancies compounded by a high-fat diet (HFD). In PRLR-deficient β-cells, there is a reduction in insulin synthesis, expression of the gene that regulates GSIS, and incretin receptor Glp1r expression and response. This results in lower insulin secretion and impaired glucose tolerance. The link between PRLR and incretin receptor expression and function in islets is novel.

Bone marrow adipose tissue (BMAT) has been linked to negative bone health outcomes, and a high level of bone marrow adipocyte accumulation is observed during aging and in individuals with diabetes and obesity. This study explores the relationships between BMAT, age, metabolic health, and the impact of their interactions on bone turnover in a cross-sectional cohort of healthy women and men. Levels of bone turnover biomarkers, procollagen type 1 N-terminal propeptide (P1NP) and β-CrossLaps, were determined alongside dipeptidyl peptidase-4 (DPP4) concentration and activity as biomarkers of metabolic health. We used magnetic resonance imaging to assess proton density fat fraction to quantify BMAT mass in healthy individuals and correlated results to sex, age, body mass index (BMI), and glycated hemoglobin A1c (HbA1c), which represents long-term glycemic control. Age was the strongest determinant of increased BMAT mass, explaining more than a third of its overall variation, as well as a robust determinant of bone turnover. A sex-specific correlation pattern was observed between BMAT and bone turnover: women displayed a trend for a positive correlation of BMAT, which depended on age. In men, BMAT mass correlated significantly, but inversely, with both biomarkers, which was also age-dependent. DPP4 concentration and activity were positively associated with P1NP in both sexes, and these relationships were independent of age, BMI, or HbA1c. These findings indicate that the impact of BMAT on bone turnover may be age-dependent, whereas metabolic regulator DPP4 is linked to bone turnover independently of metabolic health or aging.NEW & NOTEWORTHY Our findings highlight the central role of bone marrow adipose tissue in the relationship between bone health, age, and metabolism. Increased marrow adipocytes produce endocrine signals, such as dipeptidyl peptidase-4, which modulate these associations. We show that women and men have distinct associations between bone turnover, age, and bone marrow adipocytes.

Hemoglobin (Hb) levels are commonly measured to assess health and oxygen transport. Although levels outside the reference interval indicate anemia or polycythemia, higher Hb levels within the referenced interval have been linked to adverse cardiometabolic traits in adults. As cardiometabolic traits are exacerbated by aging, associations in older subjects are susceptible to confounding effects such as comorbidities, medications, and lifestyle factors, for example, smoking. Our aims were to 1) cross-sectionally establish whether Hb levels within the Finnish reference interval are associated with anthropometric and cardiometabolic traits including >100 systemic metabolites in 16-yr-old adolescents of the Northern Finland Birth Cohort 1986 (n = 5,795), 2) evaluate the effects of sex and smoking on these associations by restriction, and 3) establish whether Hb levels at age of 16 are associated with metabolic traits at age of 33. Regression models were used to further account for confounding factors. Hb levels were associated positively with body mass index and other anthropometric measures, leucocyte count, glucose, insulin, total cholesterol, LDL cholesterol, triglycerides, small-to-extremely-large VLDL particles, alanine, creatinine, and testosterone levels, and blood pressure and heart rate at the age of 16. Associations were generally stronger in males, except of those for leucocyte count and glucose and insulin levels, which were stronger in females. Adjusting for smoking weakened the associations. Longitudinally, Hb levels at the age of 16 associated positively with anthropometric measures at the age of 33. These data suggest that higher Hb levels, even within the reference interval, may reflect early cardiometabolic risk, with sex and smoking influencing the strength of associations.NEW & NOTEWORTHY Hb levels, one of the most commonly measured laboratory tests, could be used beyond anemia in assessment of cardiometabolic health already in adolescence; higher Hb levels within the reference interval are associated with an increased risk.

Nesting materials are used to enhance animal welfare in laboratory settings, yet their physiological impact, particularly on energy metabolism, remains undercharacterized. Here, we investigated the effect of three commonly used nesting materials (nestlet, Enrich-n'Nest, and Bed-r'Nest) and the presence versus absence of nesting on metabolic parameters in male mice housed at thermoneutral (30°C), standard (22°C), and cold (10°C) temperatures. Using indirect calorimetry, we continuously monitored respiratory exchange ratio (RER), food intake, and water intake. Within each thermal condition, the presence of nesting compared with no nesting was associated with reduced oxygen consumption (V̇o₂) at 22°C and an attenuation of thermogenic demand at 10°C, whereas nesting has minimal effects at 30°C. In contrast, the type of nesting material did not differentially affect V̇o₂, RER, or ingestive behavior at any temperature. Environmental variables, including temperature stability and relative humidity, were closely monitored and remained within standard ranges throughout the experiments. Together, these findings demonstrate that although nesting availability modulates metabolic demand in a temperature-dependent manner, commonly used nesting materials do not introduce meaningful variability in metabolic cage studies. These findings support the continued use of these three nesting materials in metabolic phenotyping and highlight the importance of transparent reporting of housing and enrichment conditions to improve reproducibility in preclinical metabolic research.NEW & NOTEWORTHY Nesting availability, but not nesting material type, modulates energy metabolism in individually housed male mice in a temperature-dependent manner. Nesting reduces metabolic demand at standard housing temperature, with minimal impact at thermoneutrality. These findings support the use of common nesting materials and highlight the importance of reporting environmental enrichment to improve rigor and reproducibility in metabolic studies.

The objective of this is to compare the effects of diet restriction and semaglutide treatment on body composition (BC), energy expenditure (EE), and metabolic adaptation (MA) in Göttingen Minipigs as a model for human obesity. Diet-induced obese Göttingen Minipigs were divided into three groups (n = 8): a control group receiving vehicle and fed ad libitum, a group treated with the GLP-1 receptor agonist (GLP-1RA) semaglutide and fed ad libitum, and a diet-restricted group receiving vehicle and weight-matched the semaglutide group. BC, EE, and plasma parameters were measured at baseline and after 10 wk; tissue mitochondrial respiration and myosin conformation were measured after 10 wk. Diet-restricted minipigs gained 6.8% (P < 0.01) more body fat compared with semaglutide, mediated by a greater loss of fat-free mass (4.3 kg, P < 0.05) and a tendency for a higher fat mass gain (P = ns). Diet restriction led to significantly decreased EE compared with the control group (-273 kcal/day, P < 0.05), but no differences between groups were observed when adjusting EE for changes in BC. Energy balance modeling revealed significant MA in the diet-restricted animals (P < 0.01) compared with both control and semaglutide groups. Diet restriction was further associated with decreased proton leak and resting myosin ATP consumption in muscle. Semaglutide treatment improved BC and EE outcomes compared with diet restriction despite similar weight trajectories. Furthermore, semaglutide treatment prevented specific energy-conserving changes in tissues, thus highlighting novel mechanisms regulating energy balance during GLP-1RA treatment.NEW & NOTEWORTHY Specific energy-conserving mechanisms and metabolic adaptation challenge weight loss efficiency and maintenance, and promote weight regain after diet restriction. Less is known about these mechanisms after pharmacologically induced weight loss. For the first time in a minipig model of obesity, the research demonstrated how GLP-1 receptor agonist (GLP-1RA) treatment, compared with a weight-matched diet-restricted group, positively influenced body composition, energy expenditure, mitochondrial thermogenesis, and myosin ATPase activity. These novel mechanisms of energy expenditure may have potential as future drug targets.

Obesity is a chronic disease, representing a significant health problem worldwide. Unhealthy eating habits and sedentarism are key contributors to the development of obesity. Dietary and exercise strategies are the first-line therapies for weight loss or maintenance and have proven effective in controlling weight. However, long-term adherence is challenging, and rapid weight regain often follows intervention cessation. In mice, time-restricted feeding (TRF) and exercise (EXE) independently prevent weight gain and maintain metabolic health, yet weight regain is observed upon cessation. Whether combining TRF and EXE provides longer-lasting benefits remains unclear. Here, we assessed weight and metabolic parameters in Swiss male mice fed with a high-fat diet (HFD) during an 8-wk intervention of TRF (8-h food access in the active phase) or TRF combined with EXE (60-min treadmill running daily) and after cessation and transfer to ad libitum feeding. TRF and EXE interventions successfully mitigate weight gain, improve glycemic homeostasis, and attenuate lipid accumulation in the liver and adipose tissue hypertrophy compared to mice fed HFD ad libitum. However, cessation of both strategies led to rapid weight regain, impaired glycemic control, and increased circulating lipid levels. Although the combination of TRF and EXE led to the lowest body weight and best metabolic health, this group showed no protection against the metabolic impairments observed after TRF cessation alone. In conclusion, TRF and EXE are complementary strategies for managing metabolic health, but cessation of these interventions leads to rapid weight regain and metabolic deterioration, with only partial preservation of select metabolic adaptations. These findings underscore the critical need for sustained adherence to lifestyle interventions in obesity management.NEW & NOTEWORTHY This study demonstrates that combining time-restricted feeding with aerobic training improves weight and metabolic health in Swiss mice fed a high-fat diet. Importantly, we show that most metabolic benefits are lost after intervention cessation. However, insulin sensitivity and aspects of hepatic lipid metabolism are partially maintained after cessation of the intervention. These findings provide new insight into the durability of metabolic improvements induced by lifestyle interventions and highlight the potential of combined dietary and exercise strategies to counteract diet-induced obesity and metabolic dysfunction.

Aging is associated with reduced lean and bone mass, as well as alterations in gut microbiota composition. We previously demonstrated that gut microbiota composition differs between young adult and old mice, and that transplanting gut microbiota from old donors into young germ-free mice reduces lean mass, but not bone mass, compared with transplantation from young adult donors. In this study, we investigated whether the reduced lean and bone mass observed in old mice could be restored through gut microbiota transplantation from young adult donors. Old mice (18-mo old) were treated with antibiotics to deplete their gut microbiota and subsequently transplanted with gut microbiota from either young adult (5-mo old) or old (21-mo old) donors. Recipient mice colonized with gut microbiota from young adult donors showed distinct beta and alpha diversity compared with those colonized with gut microbiota from old donors, demonstrating successful transplantation. However, no differences in lean or bone mass were observed between old mice transplanted with gut microbiota from young adult donors and those receiving gut microbiota from old donors. In conclusion, our findings demonstrate that gut microbiota composition differs in mice transplanted with young adult compared with old gut microbiota but neither reduced lean mass nor reduced bone mass in old mice can be restored through gut microbiota transplantation from young adult donors.NEW & NOTEWORTHY Aging is associated with reduced lean and bone mass and changes in gut microbiota (GM). We tested whether transplanting young adult GM could reverse these age-related conditions in old mice. GM transplantation resulted in distinct GM compositions between mice receiving young adult versus old donor GM, but neither lean nor bone mass was restored in old mice. These findings suggest that GM from young adult mice cannot restore musculoskeletal deficits in aging.

Irritable bowel syndrome (IBS), a common disorder of gut-brain interaction, has been increasingly associated with metabolic dysfunction and cardiometabolic risk. This study aimed to comprehensively assess cardiometabolic risk factors in individuals with IBS and to characterize their metabolic profiles in comparison with those of healthy and diabetic cohorts. First, in a retrospective database analysis, cardiometabolic risk factors of patients with IBS (n = 582,377) were compared with healthy controls (HCs) (n = 1,492,376). Following propensity score matching (n = 492,468), cardiometabolic parameters were analyzed during a follow-up period of 1-24 mo postindex. Second, a total of 234 individuals underwent comprehensive metabolic phenotyping using state-of-the-art nuclear magnetic resonance spectroscopy, comparing blood profiles of patients diagnosed with type 2 diabetes (T2D), IBS, and HC. We observed an increased cardiometabolic risk profile in patients with IBS compared with HC, characterized by higher mean body mass index, higher triglyceride levels, lower high-density lipoprotein cholesterol, and higher hemoglobin A1c levels. Odds ratios (ORs) were significantly increased in IBS, particularly for chronic hyperglycemia (OR = 16.32; P < 0.001). Results were confirmed by deep metabolic phenotyping, revealing a metabolic tendency in patients with IBS toward profiles characteristic of T2D by alterations in amino acid (glycine, histidine, and phenylalanine), glucose (glucose, lactate, and pyruvate), and lipid metabolism (parameters related to very low-density lipoproteins). Our findings confirm that IBS is linked to a distinct cardiometabolic risk profile and reveal metabolic associations relevant to T2D.NEW & NOTEWORTHY We identified a distinct cardiometabolic risk profile in patients with IBS, characterized by elevated BMI, triglycerides, HbA1c, and reduced HDL-C levels. Metabolic phenotyping reveals a pattern in patients with IBS comparable with T2D profiles, including altered amino acid, glucose, and lipid metabolism.

Skeletal muscle possesses a remarkable capacity for regeneration, which is largely orchestrated by muscle satellite cells (MuSCs), a population of tissue-resident stem cells. Upon injury, these cells sense cues from their niche, transition from quiescence to activation, and subsequently undergo proliferation and differentiation to restore damaged myofibers. Although cholesterol, an essential component of the plasma membrane, is critical for cell growth and membrane dynamics, the regulatory landscape governing cholesterol metabolism during muscle regeneration remains poorly defined. In this study, we investigated the temporal expression patterns of lipid-associated genes during regeneration and identified a pronounced upregulation of liver X receptor (LXR) target genes 3 days postinjury, implicating oxysterol-mediated signaling as a potential modulator of the regenerative process. Furthermore, gas chromatography-mass spectrometry (GC-MS) analyses revealed elevated levels of oxysterols, specifically 4β-hydroxycholesterol and 25-hydroxycholesterol, in response to muscle injury induced by cardiotoxin (CTX) or barium chloride (BaCl₂). Complementary in vitro experiments demonstrated that the administration of LXR agonists promoted myogenic differentiation in cultured skeletal muscle cells, whereas pharmacological inhibition of LXR signaling impaired this process. Importantly, LXR activation attenuates lipopolysaccharide (LPS)-induced inflammatory responses in myocytes and concurrently enhances anabolic signaling through the Akt-mTOR axis, leading to increased protein synthesis. Collectively, these findings highlight the previously underappreciated role of cholesterol-derived metabolites in coordinating muscle regeneration, suggesting that LXR-mediated transcriptional programs simultaneously govern differentiation, inflammation, and biosynthetic capacity in regenerating skeletal muscle.NEW & NOTEWORTHY This study aimed to investigate the role of cholesterol-derived metabolites in skeletal muscle regeneration. We found a marked upregulation of liver X receptor (LXR) target genes during muscle regeneration, with increased oxysterol levels (4β-hydroxycholesterol and 25-hydroxycholesterol) after injury. LXR activation promotes myogenic differentiation, inhibits LPS-induced inflammation, and enhances protein synthesis through the Akt-mTOR pathway. These results revealed that LXR is a key regulator of muscle regeneration, influencing differentiation, inflammation, and anabolic processes via cholesterol metabolism.

Severe diet- and exercise-induced energy deficit (SED) suppresses androgen production in healthy men, altering metabolism and driving muscle loss. The gut microbiota modulates host metabolism, yet the community's response to SED and any role of androgen hormones are unclear. Herein, healthy, physically-active men were randomized to receive 200mg/wk testosterone enanthate (n = 24) or placebo (n = 26) during a 28-day residential intervention that restricted energy intake and increased energy expenditure inducing a ~2000 kcal/d SED. Multi-omic analyses revealed altered gut microbiota composition, reduced fecal short-chain fatty acids (SCFA), and shifts in bacterial metabolic pathways toward lipid utilization and mucin degradation during SED, suggesting adverse effects of SED on gut microbiota metabolic functions. Testosterone administration preserved certain SCFA-producing taxa and bioenergetic pathways without fully counteracting effects of SED indicating a limited but potentially important interplay between androgen status and the gut microbiota under conditions of SED.