American journal of physiology. Endocrinology and metabolism最新文献

This review explores the various biological changes that occur during the aging process, elucidating the fundamental pathological mechanisms leading to a decline in muscle integrity and functionality. A primary focus of the review is the occurrence of fat infiltration within skeletal muscle, a phenomenon that becomes increasingly prevalent with advancing age. The study assesses the implications of fat infiltration on skeletal muscle performance, along with the regulatory signaling mechanisms potentially influenced by fat accumulation. Furthermore, it addresses a variety of intervention strategies aimed at alleviating these age-related changes, including nutritional supplements, exercise regimens, and pharmacological treatments. By integrating current findings in the field and addressing existing challenges, this review aims to conduct an in-depth exploration of the intricate connection between aging and skeletal muscle health, with the goal of guiding future research and clinical practices to improve the quality of life for older adults.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-enriched receptor that regulates phagocytosis, lipid metabolism, and inflammation resolution in the brain. Loss or mutation of TREM2, including the R47H variant, impairs amyloid-β clearance and lipid handling, thereby increasing the risk and accelerating the progression of Alzheimer's Disease (AD). TREM2 signaling couples debris recognition with mitochondrial activation and fatty acid oxidation, maintaining microglial energy balance and promoting a reparative phenotype. Pharmacologic TREM2 agonists, such as AL002, DNL919, and VG-3927, enhance microglial survival, plaque compaction, and mitochondrial respiration in AD models, although clinical efficacy may depend on disease stage and metabolic fitness. Exercise training represents a complementary strategy that similarly enhances TREM2 expression, restores microglial homeostasis, and improves mitochondrial metabolism. Both aerobic and resistance exercise activate TREM2-dependent signaling pathways to reduce neuroinflammation and support synaptic integrity. Collectively, these findings highlight TREM2 as a central immunometabolic regulator and suggest that combining TREM2-targeted therapeutics with exercise may offer a synergistic strategy to slow neurodegeneration in AD.

Regular aerobic exercise decreases the risk of metabolic diseases; however, reduced physical activity may attenuate these beneficial adaptations. This study investigated the influence of a single day of reduced activity on the skeletal muscle transcriptome (RNA-Seq) and systemic metabolism surrounding an acute bout of aerobic exercise. Using a crossover design, subjects [n = 9 (7 M, 2 F), 24 ± 1 yr] exercised at 65% maximal oxygen consumption for 60 min following a day of reduced activity (IN; 3,581 ± 1,185 steps) and normal activity (A; 11,069 ± 3,631 steps). RNA-Seq from skeletal muscle biopsies was taken before and 4 h postexercise. Respiratory gas exchange analysis was completed at 20, 40, and 60 min of exercise. Blood samples for select metabolites were collected before, during, and throughout the 4 h recovery. Inactivity resulted in nine differentially expressed genes at rest, whereas exercise altered 793 and 1,403 genes in A and IN, respectively. Gene set enrichment analysis revealed an interaction of exercise and trial, which were related to inflammation, metabolism, cell cycle, and innate immunity. Respiratory exchange ratio (0.93 ± 0.04 vs. 0.91 ± 0.03; P < 0.05) and carbohydrate utilization (2.16 ± 0.79 vs. 1.96 ± 0.72 g/min; P = 0.09) were higher in the IN versus A trial at 60 min of exercise. Triglycerides were higher in the IN trial (P < 0.05), with no differences between trials observed in other measured metabolites. These findings indicate that a single day of reduced physical activity can elicit modest but significant changes in the metabolic and transcriptomic exercise response. Such alterations have implications for exercise guidelines and underscore the importance of controlling for daily step count when assessing exercise responses.NEW & NOTEWORTHY This investigation shows modest differences in the metabolic demands of an acute bout of exercise following a day of inactivity. In addition, there are differences in the skeletal muscle transcriptome at rest and in the exercise response with decreased physical activity before exercise. This study highlights the need for more research on the role of physical inactivity in the exercise response, as well as the need to control for step count before exercise response studies.

The brain has been suggested to regulate glucose metabolism in response to insulin in various tissues. As many of these findings have not been studied in humans, we aimed to assess the effects of intranasal insulin (INI) on brain and peripheral tissue-specific glucose uptake in lean, healthy men. On two separate visits, 10 volunteers received either 160 IU INI or placebo during a low-dose hyperinsulinemic, euglycemic clamp in a randomized, single-blinded, crossover design. Tissue glucose uptake was quantified using positron emission tomography (PET) and glucose analogue radiotracer 2-deoxy-2[¹⁸F]fluoro-d-glucose, with a dynamic scan starting from 40 min after INI. Tissue volumes and radiodensities were assessed with computed tomography. INI induced a global decrease in brain glucose uptake in all participants, with the magnitude of the effect correlating with the amount of visceral adipose tissue. In contrast, INI had no significant effect on skeletal muscle, liver, or adipose tissue glucose uptake. To conclude, a single dose of INI does not have a direct effect on peripheral glucose metabolism in healthy, lean men, but the previously reported hypothalamic response is accompanied by a global decrease in cerebral glucose metabolism.NEW & NOTEWORTHY In previous studies using functional magnetic resonance imaging, lean, healthy males have been shown to be most susceptible to the effects on intranasal insulin, with direct central insulin exposure also thought to enhance peripheral metabolism. However, in the current study, insulin nasal sprays failed to alter hepatic, skeletal muscle, or adipose tissue glucose metabolism but did induce a global decrease in brain glucose uptake.

The accurate estimation of daily energy requirements is important to inform athletes about their caloric needs and to prevent long-term low energy availability. Such estimations are often done by estimating energy expenditure. Recent data, including from a 200+ athlete cohort, show systematic underprediction of resting metabolic rate (RMR). Here, we tested this specifically in elite male volleyball players, who represent an underrepresented sport and a body morphology that is lacking in the literature. The purpose of this investigation is to compare the estimates of currently recommended predictive RMR equations for athletes (Harris-Benedict, Cunningham, Freire, Ten Haaf, and Tinsley) against measured RMR using high-resolution indirect calorimetry in volleyball players. Using a cross-sectional design, 22 international (tier 4) elite male volleyball players underwent evaluations of body composition, RMR, and bloodwork and completed the three-factor eating questionnaire-R18. Participants had a body mass of 93.3 ± 8.7 kg, fat-free mass of 77.5 ± 7.7 kg, and %body fat of 17.0 ± 2.2%. Our main findings were 1) the Ten Haaf [-134.9 ± 151 kcal (95% CI)], Freire [-181.4 ± 156 kcal (95% CI)], Harris-Benedict [-256.4 ± 152 kcal (95% CI)], and Cunningham [-299.8 ± 150 kcal (95% CI)] equations under predicted RMR compared with indirect calorimetry (P < 0.05), 2) the Tinsley equation was the most accurate [-126.8 ± 150 kcal (95% CI)], but moderately reliable (intraclass correlation coefficient = 0.59), at estimating RMR compared with indirect calorimetry, and 3) due to proportional bias toward heavier players, the RMR ratio < 0.90 with the Tinsley equation was not reliable to detect individual volleyball players at greater energy deficit. Future work should explore novel metabolic assessment protocols that will reliably assess energy needs of athletes high in absolute fat-free mass.NEW & NOTEWORTHY The most recently recommended predictive resting metabolic rate equations for athletes are unsuitable for heavier elite male volleyball athletes with higher FFM.

Steatotic liver disease (SLD) is a spectrum of chronic and progressive disorders. Although often associated with obesity, it can afflict individuals without obesity, including infants. We previously reported that neonatal pigs fed formulas enriched with medium-chain fatty acids (MCFAs), rather than long-chain fatty acids (LCFAs), developed steatosis by day 7 and steatohepatitis by day 14. Here, we examined hepatic regulation of lipolytic and lipogenic pathways and associated metabolic outcomes. Neonatal pigs (n = 18) were fed isocaloric formulas containing MCFAs or LCFAs for 7, 14, or 21 days. Transcript abundance of most lipolytic and lipogenic genes was greater in MCFA- than in LCFA-fed pigs, independent of feeding duration. Upregulation of lipolytic genes of MCFA-fed pigs corresponded with greater lauric (P = 0.04) and palmitic (P = 0.03) acid oxidation, and greater plasma β-hydroxybutyrate concentrations than LCFA counterparts (P = 0.06). Upregulation of lipogenic genes in the MCFA group coincided with greater hepatic medium- (C12:0, C14:0) and long- (C16:0, C16:1) chain fatty acid concentrations (P < 0.05), and greater de novo lipogenic index at all time points (P < 0.001) compared with the LCFA group. Principal component and partial least squares analyses indicated that MCFA-fed pigs clustered with upregulated lipogenic, lipolytic, and transport genes, and were associated with greater medium-chain fatty acids and hepatic fat. However, LCFA-fed pigs clustered with greater polyunsaturated fatty acids and reduced transcript abundance of these genes. These findings demonstrate that pediatric SLD pathophysiology involves metabolic adaptations where fatty acid uptake and synthesis overwhelm the liver's oxidative or export capacity, causing net lipid accumulation.NEW & NOTEWORTHY We identify a distinct metabolic state in neonatal pigs with SLD. Contrary to the prevailing paradigm, disease development and progression to the more severe steatohepatitis occur despite enhanced hepatic fatty acid oxidation and the concurrent upregulation of both lipolytic and lipogenic gene expression. This paradoxical metabolic state, where increased fatty acid oxidation fails to prevent progressive steatosis, provides new insights into early-life SLD pathophysiology.

Mitogen-activated protein kinases play an essential role in the onset of hepatic metabolic dysregulation; however, current data fail to establish a definitive role for p38. We generated a hepatocyte-specific p38α knockout (p38α KO) mouse model to investigate the role of p38α in regulating hepatic glucose and lipid metabolism following 1 wk of high-fat diet (HFD) feeding. Short-term HFD feeding increased hepatic p38 activation in mice. Hepatocyte-specific p38α KO mice were protected from the development of HFD-induced hepatic insulin resistance, in part due to the abolition of circulating interleukin-6 (IL-6). Unexpectedly, hepatocyte-specific p38α KO mice were also protected from HFD-induced peripheral insulin resistance. The liver-peripheral tissue axis underlying the onset of HFD-mediated peripheral insulin resistance may be explained by muscle fat accumulation promoted by p38α-mediated hepatic triglyceride (TG) secretion. HFD-induced activation of p38α promoted TG accumulation in the liver, potentially via enhanced expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and subsequent regulation of perilipin gene expression. Overall, our data provide compelling evidence that selective p38α inhibition may offer a new approach for the treatment of insulin resistance and hepatic steatosis.NEW & NOTEWORTHY Our data indicate that hepatocyte-specific p38α KO mice are protected from 1) HFD-induced hepatic insulin resistance in part through reduced interleukin-6 (IL-6) secretion; 2) peripheral insulin resistance via decreased hepatic triglyceride (TG) secretion and muscle fat accumulation; and 3) hepatic steatosis through reduced proliferator-activated receptor gamma (PPAR-γ) regulating perilipin gene expression. We thus provide new evidence on the potential of selective p38α inhibition as a new treatment for insulin resistance and hepatic steatosis.

Uncoupling protein 1 (UCP1), a mitochondrial protein traditionally regarded as exclusive to thermogenic adipocytes, and Ucp1-promoter-driven Cre is widely used in gene manipulation in thermogenic adipocytes. However, new evidence suggests that Ucp1-promoter-driven Cre is also active in nonadipocyte types. The presence and role of UCP1 in nonadipose tissues during development, and its potential nonthermogenic functions, remain under debate. This study systematically investigated UCP1 expression patterns from embryogenesis to adulthood using Ucp1^GFP/+ (knock-in), Ucp1^CreERT2/+ (knock-in), and Ucp1^Cre/+ (transgenic) mice crossed with Ai9-tdTomato-Red mice, complemented by single-cell RNA sequencing and immunostaining analyses. Ucp1^{CreERT2/CreERT2} knockout mice were used to evaluate the developmental consequences of UCP1 deficiency. Significantly, UCP1 expression initiated in nonthermogenic tissues by embryonic day 10.5, before adipose tissue formation, notably in the brain, eye, ear, mammary gland, kidney, and reproductive systems. UCP1 was more broadly expressed in nonadipose tissues during embryonic stages compared to adulthood, particularly in the epithelial cells of these nonadipose tissues. UCP1 knockout mice exhibited retinal developmental defects, suggesting physiological roles for UCP1 beyond thermogenesis in nonadipose tissues. This study highlights that using Ucp1-promoter-driven tamoxifen-inducible Cre can minimize off-target effects in gene manipulation of thermogenic adipocytes compared with the traditional transgenic Cre strategy.NEW & NOTEWORTHY Our findings reveal UCP1 expression begins from E10.5, particularly in the brain, kidney, ear, eye, mammary gland, and reproductive system. During embryonic development, UCP1 expression is more prevalent in nonadipose tissues, compared to adulthood, especially in epithelial cells. Notably, UCP1-knockout mice exhibit developmental defects in retinas, suggesting UCP1 has physiological functions beyond thermogenesis. Our study highlights using Ucp1-promoter-driven tamoxifen-inducible Cre can minimize off-target effects in gene manipulation within thermogenic adipocytes compared to traditional Cre methods.

Cocaine- and amphetamine-regulated transcript peptide inhibits food and water intake in rodents and there is evidence that the peptide interacts with the previously orphaned G protein-coupled receptor G protein-coupled receptor (GPR160). In addition, the peptide transmits pain signals in spinal cord and loss of Gpr160 expression blocks spinal nerve injury pain perception. With the same animal model as that used to demonstrate the necessity of Gpr160 expression for pain perception, we examined food and water intakes under ad libitum conditions and following acute stress. We report that total daily food and water intakes in knockout animals do not significantly differ from those in Gpr160-expressing controls, but meal patterning is altered. On the other hand, food intake following an acute stress is altered. We conclude that in mice activation of GPR160 is not essential for unstimulated food and water ingestion, but that loss of receptor expression is sufficient to change the patterning of ingestive behavior.NEW & NOTEWORTHY Cocaine- and amphetamine-regulated transcript peptide (CARTp) acts via a G protein-coupled receptor (GPR160) to induce pain and inhibit feeding. GPR160 deletion prevents the perception of neuropathic pain and alters basal and stress-induced food intake. Although GPr160 is necessary for the sensation of painful stimuli, it appears to only affect meal patterning, but not total food intake. Antagonists of GPR160 may be useful for pain management without deleterious effects on daily food intake.

Recurrent pregnancy loss (RPL) is a multifactorial condition, with nearly half of cases remaining unexplained, and maternal insulin resistance is identified as a significant contributor. This study examined the role of salt-inducible kinase 1 (SIK1) in RPL patients associated with insulin resistance using villi samples, in vitro trophoblast models, and an insulin-resistant mouse model. Our results revealed that a marked increase in miscarriage risk was observed in women with a higher value of homeostatic model assessment for insulin resistance (>2.41). SIK1 expression was elevated in the villous tissues of RPL patients with insulin resistance, as well as insulin-treated trophoblast models. Overexpression of SIK1 impaired trophoblast migration and invasion by downregulating matrix metalloproteinase-2 and matrix metalloproteinase-9 and disrupted decidual natural killer cell-mediated vascular remodeling. Cocultured decidual natural killer cells exhibited altered cytokine expression, leading to endothelial dysfunction. In vivo, insulin-resistant mice showed elevated placental SIK1 expression, reduced pregnancy success, and defective spiral artery remodeling. These findings suggest that SIK1 activation driven by insulin resistance impairs trophoblast and decidual natural killer cell functions, thereby contributing to recurrent pregnancy loss.NEW & NOTEWORTHY Insulin resistance has been clinically linked to RPL, but mechanisms at the maternal-fetal interface remain unclear. This study combines clinical villous samples, in vitro trophoblast-dNK-endothelial coculture systems, and an insulin-resistant mouse model to demonstrate that SIK1 is upregulated in RPL patients with IR and impairs trophoblast invasion and cytokine regulation and endothelial remodeling. These findings implicate SIK1 in immune-vascular dysregulation, offering a mechanistic link between maternal metabolic stress and placental vascular dysfunction.