American journal of physiology. Endocrinology and metabolism最新文献

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.

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.

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.

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.

Aerobic fitness is associated with greater skeletal muscle insulin sensitivity with regard to glucose uptake. Whether fitness is associated with an improvement in the insulin regulation of adipose tissue lipolysis is unknown. We collated adipose insulin sensitivity, body composition, and fitness data from six of our previously published and two of our unpublished protocols. Adipose tissue insulin resistance index of palmitate (ADIPO-IR_palmitate) data were available for 340 volunteers, and the insulin concentration resulting in a 50% suppression of palmitate rate of appearance (FFA_palmitate IC₅₀) measured using the insulin clamp technique was available for 108 volunteers. Pearson's correlation and multiple linear regression analysis were performed to assess the relationship between the independent variables of aerobic fitness [peak oxygen consumption (V̇o_2peak), mL kg·FFM^-1·min^-1], age, sex, body mass index (BMI), visceral adipose tissue (VAT), body fat, percent body fat, and the dependent variables ADIPO-IR_palmitate and FFA_palmitate IC₅₀. Factors that were univariately correlated (P < 0.001) with ADIPO-IR_palmitate and FFA_palmitate IC₅₀ were BMI, percent body fat, body fat, and VAT. Fitness correlated negatively with ADIPO-IR_palmitate and FFA_palmitate IC₅₀. Stepwise regression analysis showed that fitness independently predicted ADIPO-IR_palmitate and FFA_palmitate IC₅₀ after adjusting for the other significant factors. These findings suggest that aerobic fitness may promote metabolic health through positive effects on adipose tissue. Clinical Trial Registration: NCT00254371; the other protocols were not considered clinical trials at the time they were conducted.NEW & NOTEWORTHY Greater degrees of aerobic fitness are associated with greater insulin-mediated muscle glucose uptake. Insulin regulates adipose tissue lipolysis, whether aerobic fitness affects insulin's ability to regulate lipolysis is unknown. We found that greater fitness is associated with improved adipose tissue insulin responsiveness independent of age, sex, BMI, visceral adipose tissue, body fat (kg), percent body fat, and adipocyte size. This suggests that exercise, if it improves fitness, may improve both adipose tissue and muscle function.

Hashimoto's thyroiditis (HT) is a prevalent autoimmune disease marked by lymphocytic infiltration and progressive destruction of the thyroid gland. The pathogenesis involves cytotoxic T lymphocytes, whereas regulatory T cells (Tregs), identified by the transcription factor Forkhead box P3 (FOXP3), are crucial for maintaining self-tolerance. This study aimed to investigate the composition of HT' lymphocyte infiltrate and the expression of FOXP3 and PD-L1 within HT patients' thyroid tissue, aiming to clarify their roles in this chronically activated immune environment. This cross-sectional study analyzed surgical thyroid specimens from 18 patients with HT and 12 nonautoimmune controls. Immunohistochemistry was used to evaluate the expression of CD4⁺, CD8⁺, CD20⁺, FOXP3, and PD-L1 markers in the tissue. The HT group had significantly higher expression of CD4⁺, CD8⁺, and CD20⁺ lymphocytes. Although CD25⁺ expression was similar between groups, FOXP3 was positive in 100% of HT samples versus only 8.3% of controls. HT was associated with PD-L1 follicular cell expression in both the cytoplasm and cell membrane, a pattern distinct from the predominantly cytoplasmic expression in controls. In conclusion, this study demonstrates that HT involves a dense intrathyroidal infiltrate of effector T cells, B cells, and FOXP3⁺ Treg cells. The higher prevalence of FOXP3 without a corresponding higher prevalence of CD25⁺ suggests a population of chronically activated Tregs within the inflamed gland. The distinct expression pattern of PD-L1 in follicular cells indicates that the PD-1/PD-L1 pathway is actively engaged, possibly as a protective feedback mechanism against autoimmune destruction. These findings help clarify the local immunoregulatory network in HT and highlight Tregs and the PD-1/PD-L1 axis as promising targets for future therapeutic interventions.NEW & NOTEWORTHY This study provides insight into the local immune environment of Hashimoto's thyroiditis by analyzing the lymphocytic infiltrate in thyroid tissue directly. Key novel findings are the increased prevalence of FOXP3⁺ lymphocytes without a corresponding increase in CD25⁺ cells, suggesting a population of chronically activated regulatory T cells. It also identifies a distinct PD-L1 expression pattern in follicular cells (both membrane and cytoplasm), suggesting a protective feedback mechanism against autoimmune attack.

The effects of Roux-en-Y gastric bypass (RYGB) on the gut-brain axis remain poorly understood. This study specifically explores phenotypic changes in vagal afferent neurons in male obese C57BL/6J mice following RYGB. Our results show that RYGB induced the expression of activating transcription factor 3 (Atf3) mRNA-a well-established marker of axonal injury-in a subset of vagal sensory neurons. In addition, RYGB led to a significant reduction in both the proportion of vagal afferents expressing the glucagon-like peptide 1 receptor (GLP1R) and the overall Glp1r mRNA levels in the nodose ganglion. Nerve transection experiments replicated these changes, suggesting that axonal injury alone may account for the observed phenotypic alterations in vagal afferent neurons following RYGB. Electrophysiological recordings further revealed that acute administration of exendin-4, a GLP1R agonist, significantly enhanced afferent vagus nerve firing. Interestingly, this response was notably exaggerated in RYGB animals and those with injured gastric vagus nerves. Collectively, these findings provide both molecular and electrophysiological evidence that RYGB induces vagal neuropathy, characterized by reduced Glp1r expression and heightened sensitivity to GLP1.NEW & NOTEWORTHY Roux-en-Y gastric bypass in obese mice triggered markers of vagal nerve injury, reduced Glp1r-expressing vagal afferents, and lowered Glp1r mRNA in the nodose ganglion. Nerve injury experiments reproduced these effects. Despite reduced receptor expression, GLP1R agonist-evoked vagal firing was exaggerated after RYGB or vagal injury. Overall, the findings indicate RYGB causes vagal neuropathy with diminished Glp1r expression but heightened GLP1 sensitivity.

Enteroendocrine cells (EECs) are specialized cells located throughout the gastrointestinal (GI) tract, where they have an essential role in regulating various physiological processes related to digestion, metabolism, and gut physiology. EECs secrete different hormones in response to food intake and the presence of nutrients in the gut, which regulate digestion, appetite, insulin secretion, and energy balance. One of the most well-studied hormones is glucagon-like peptide-1 (GLP-1), which is produced by L cells in both the small intestine and the colon. Colonic GLP-1-secreting L cells are not immediately exposed to food and are thus less likely to be responsible for the release of GLP-1 that occurs shortly after ingestion of a meal. Here we sought to determine the role of GLP-1 produced from the distal gut, by generating mice with a deletion of the gene encoding proglucagon (Gcg) in the distal gut and analyzed the effects on body weight, glucose metabolism, and gut transit. Deletion of Gcg in the distal gut reduced circulating levels of GLP-1 but did not affect glucose metabolism or insulin levels on a chow diet or body weight gain or glucose metabolism on a Western-style diet. However, we observed that deletion of distal gut GLP-1 resulted in faster small intestinal transit in female but not male mice. We successfully developed a mouse model that can target L cells in the distal gut and demonstrate that GLP-1 from the distal gut is dispensable for weight and glucose regulation, whereas it regulates gut motility in female mice.NEW & NOTEWORTHY Previous studies have suggested that GLP-1 from the distal gut may be of importance for regulation of glucose metabolism although the contribution from ileal and colonic GLP-1 has not been separated. In this study, we established a mouse model to more specifically dissect the role of colonic GLP-1 and demonstrate that the physiological role of GLP-1 from the colon does not include the well-established metabolic functions but rather slows small intestinal transit.

The enzyme selenocysteine (Sec) lyase (SCLY) decomposes Sec releasing selenide for the synthesis of selenoproteins, which contain Sec in their primary structure and participate in strong redox reactions, maintaining redox balance. We previously showed global disruption of the Scly gene (Scly KO) in mice leads to obesity. Targeted deletion of Scly in Agrp neurons enhances energy expenditure and brown adipose tissue (BAT) activation, augmenting leanness. We hypothesized that Scly KO mice develop obesity due to failure of BAT-controlled mechanisms of energy expenditure due to redirection of Sec to an alternative pathway. We analyzed BAT from male Scly KO mice on Se-adequate (0.25 ppm) and Se-deficient (0.08 ppm) diets for morphology, Se content, selenoprotein expression, thyroid hormones, and additional Sec-utilizing pathways. We found that BAT of Scly KO mice was enlarged, with lower Se levels, and substantial whitening on a Se-adequate diet. This phenotype worsened on low Se and coincided with a mild impairment in adapting to cold exposure. BAT whitening coincided with an increase in triglycerides and reduced 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) and cholesterol. BAT selenoproteins regulating energy metabolism DIO2, GPX1, and GPX4 were significantly decreased. DIO2 reduction corresponded with an increase in thyroxine (T4), thyroid stimulating hormone (TSH), and reduction in heat-producer uncoupling protein 1 (UCP1). Downregulation of GPX4 did not affect ferroptosis in the BAT. Therefore, the whitened BAT of the Scly KO mouse is a multifactorial process involving the disruption of BAT function through changes to selenoproteins involved in energy metabolism.