American journal of physiology. Endocrinology and metabolism最新文献

Childhood obesity, especially in girls, often correlates with advanced puberty and long-term comorbidities. Among the central circuits controlling energy homeostasis, hypothalamic lipid sensing pathways, involving free fatty-acid receptors (FFARs), peroxisome proliferator-activated receptors (PPAR) and the bile-acid (BA) receptor, TGR5, have been recognized as major players, with putative pathogenic roles in obesity and its complications. However, their contribution to pubertal regulation and obesity-induced pubertal alterations remains largely unexplored. We describe herein changes in the hypothalamic profiles of specific lipid species, including certain fatty-acyls, BA derivatives and several glycerol(phospho)lipids, during the juvenile-pubertal transition and conditions of overweight linked to precocious puberty in female rats. Hypothalamic expression of the FFAR, Gpr84, as well as Ppar-γ and Tgr5 gradually increased during infantile-prepubertal transition, while early-overfeeding increased hypothalamic mRNA levels of the FFARs, Gpr43 and Gpr84. Expression of Gpr84, Ppar-α and Tgr5 was documented in FACS-isolated Kiss1 neurons from juvenile and pubertal female mice. Central pharmacological gain- and loss-of-function manipulations of Gpr84-, PPAR- or TGR5-signaling in prepubertal lean and early-overfed female rats resulted in specific changes in pubertal timing. In lean rats, central blockade of PPAR-γ/α delayed puberty onset, while in early-overfed rats, central stimulation of TGR5 signaling partially prevented obesity-induced advanced puberty; effects marginally observed also after Gpr84 inhibition. Our results disclose the role of brain lipid-sensing pathways in the control of puberty, with a variable contribution of central FFAR-, PPAR- and TGR5-signaling depending on the maturational and nutritional status.

Mitochondrial oxysterols, cholestenoic acid (CA), 25-hydroxycholesterol (25HC), and 27-hydroxycholesterol (27HC), are potent regulators involved in many important biological events. This study aimed to investigate the metabolic pathways of these oxysterols and their roles between hepatocytes and macrophages. LC-MS/MS analysis showed a novel regulatory molecule, 3β-sulfate-5-cholestenoic acid (3SCA), following the addition of CA in media culturing hepatocytes. Further study showed that 3SCA could also be derived from 27HC. In comparison, 25HC was converted to 25HC3S, which mostly remained in the cells and nuclei. The functional study showed that 3SCA significantly downregulated the expression of genes involved in lipid metabolism in hepatocytes and suppressed gene expression of proinflammatory cytokines induced by lipopolysaccharide in human macrophages. Based on the results, we conclude that 3SCA acts as a secretory regulator for the regulation of lipid metabolism and inflammatory responses in hepatocytes and macrophages. These findings shed light on understanding the unique metabolic pathways of these oxysterols and their possible roles in liver tissues.NEW & NOTEWORTHY This study identifies a novel oxysterol metabolite, 3β-sulfate-5-cholestenoic acid (3SCA), secreted by hepatocytes, which regulates lipid metabolism and inflammatory responses in hepatocytes and macrophages. These findings reveal previously unknown metabolic pathways of mitochondrial oxysterols and their roles in the progression and recovery of metabolic dysfunction-associated steatotic liver disease (MASLD), offering novel insights into potential therapeutic targets.

Offspring exposed to metformin treatment for gestational diabetes mellitus (GDM) experience altered growth patterns that increase the risk for developing cardiometabolic diseases later in life. The adaptive cellular mechanisms underlying these patterns remain unclear. Therefore, the objective of this study was to determine whether chronic in utero metformin exposure associated with GDM treatment elicits infant cellular metabolic adaptations. In a cross-sectional design, 22 pregnant women diagnosed with GDM and treated exclusively with metformin (Met; n = 12) or diet (A1DM; n = 10) were compared. Umbilical cord-derived mesenchymal stem cells (MSCs) were used as a model to study infant metabolism in vitro. OXPHOS and citrate synthase content were assessed by Western blot and intracellular lipid content was measured by Oil Red-O staining. Substrate oxidation and insulin action were measured with ¹⁴C radiolabeled glucose and oleate at baseline and following a 24-h lipid challenge. Mitochondrial respiration was assessed by high-resolution respirometry. Although no differences in infant birth measures were observed between groups, MSC outcomes revealed lower oleate oxidation rates (P = 0.03) and lower mitochondrial capacity (P = 0.009) among Met-MSCs. These findings suggest differences in energy metabolism may be present at birth among offspring exposed to metformin in utero. Lower oleate oxidation and mitochondrial capacity in infant MSC may contribute to altered growth patterns that have been reported among offspring of metformin-treated pregnant women with GDM.NEW & NOTEWORTHY Mesenchymal stem cells (MSCs) of infants born to women with gestational diabetes mellitus (GDM) treated by metformin display lower rates of oleate oxidation despite no limitations in lipid availability compared with GDM treated by diet. Mitochondrial capacity was also lower among infant MSCs from metformin-treated GDM.

Leptin is a hormone produced by adipocytes that plays a crucial role in regulating energy homeostasis and body mass. Despite its close correlation with body fat, up to ∼40% of variation in plasma leptin concentration remains unexplained, allowing for the classification of a distinct "leptin phenotype." This leptin phenotype-characterized by either relatively high or relatively low leptin concentration relative to an individual's level of body fat-presents an intriguing opportunity to test whether relatively higher (compared with lower) leptin concentrations differentially affect energy expenditure, metabolic adaptation, and susceptibility to weight change in response to energy balance perturbations. To test this hypothesis, we characterized the energy expenditure and weight change response between the two leptin phenotypes (relatively high vs. low) using three distinct experimental contexts: a cross-sectional analysis (n = 104), acute (24-h) perturbations with fasting and overfeeding (n = 77), and chronic perturbations with 24-mo caloric restriction (n = 144) or 8-wk overfeeding (n = 28). Leptin phenotype did not explain variations in energy expenditure responses either in cross-sectional analyses or in response to acute or prolonged energetic stressors. Moreover, leptin phenotype was not a determinant of weight change in response to energy restriction or surplus, or subsequent weight recovery. These results suggest that classifying individuals based on a leptin phenotype does not allow to detect differential susceptibility to energy expenditure adaptations or weight change.NEW & NOTEWORTHY Leptin is linked to body fat, but unexplained variation remains. This study challenges the idea that distinct leptin phenotypes-characterized by relatively high or low leptin concentration for a given level of body fat-affects energy expenditure or weight change in response to acute or prolonged energy stressors. We found no association between leptin phenotypes and energy expenditure or weight change either cross-sectionally or in response to acute or prolonged over- or underfeeding.

Insufficient or imbalanced protein can disrupt gut microbiota, potentially compromising gut barrier function and increasing health risks. Herein, we investigated the effects of protein restriction on cecal microbiota and colon morphofunction in male mice. From 30 to 120 days of age, C57Bl/6 mice were fed a control protein diet [14% protein, control (C) group] or a low-protein diet [6% protein, protein-restricted (R) group]. At the end of the experimental period, R mice exhibited typical features of undernutrition, such as reduced body weight, hypoalbuminemia, and hypoproteinemia. In addition, despite the hyperphagia displayed in the R group, these mice presented a decreased amount of excreted feces and less energy content in feces. Cecal microbiota analysis demonstrated that protein restriction led to reductions in Shannon and Simpson indices and, therefore, dysbiosis. This effect was accompanied by morphological modifications in the proximal colon of R mice, such as 1) reduction in the total area of neurons of myenteric plexus; 2) increased number of goblet cells, with mucin droplets less developed; 3) reductions in crypt depth and diameter; 4) decreases in gene expressions for mucins and in the tight junction proteins expression; 5) enhanced paracellular permeability and expression of pro-inflammatory cytokines (tumor necrosis factor α, toll-like receptor 4, interferon γ, interleukin 1β, and interleukin 6), decreased anti-inflammatory cytokines (interleukins 4 and 10) in the colon, and increased plasma LPS binding protein concentrations. Therefore, protein restriction induced gut dysbiosis and may result in structural and functional negative impacts on the proximal colon barrier against luminal bacteria.NEW & NOTEWORTHY Prolonged postweaning protein restriction induced gut dysbiosis and led to a reduced neuron area in the myenteric plexus, with increased but underdeveloped goblet cells. Protein restriction decreased colonic crypt depth and diameter, and increased paracellular permeability due to lower expression of mucin-related genes and tight junction proteins. The diminished barrier function resulted in systemic inflammation, evidenced by elevated plasma LPS-binding protein and pro-inflammatory markers in the colon.

The central nervous system (CNS) senses and integrates blood glucose status, regulating its levels through communication with peripheral organs. Since traditional wisdom holds that the hypothalamus primarily controls glucose homeostasis, the brainstem, although less studied, has been emerging as a key player in blood glucose metabolism. Although the brainstem is reciprocally wired with the hypothalamus, their interactions are crucial for glucose control. Here, we focus on classic discoveries and recent advancements of hypothalamic and brainstem nodes that regulate glucose homeostasis. Based on the current progress and development for central regulation of blood sugar, we propose that the circuitry and cellular mechanisms for how hypothalamus and brainstem coordinate in blood sugar regulation are crucial; hence, a deeper understanding of both nuclei could shed light on a future cure for diabetes.

Fibroblast growth factor 19 (FGF19) signaling in the brain is associated with body weight loss, reduced food intake, and improved glycemic control in obese mice through unclear mechanisms. Here, we investigated the effects of central FGF19 administration on peripheral tissues, focusing on adipose tissue and its contributions to body weight loss. Using single-cell RNA sequencing of the adult murine hypothalamus, we found that FGF19 has the potential to target multiple cell populations, including astrocytes-tanycytes, microglia, neurons, and oligodendrocytes. Central delivery of FGF19 decreased body weight gain and ameliorated glucose-insulin homeostasis in diet-induced obese (DIO) mice. These results were accompanied by increased energy expenditure and reduced peripheric inflammation. Notably, these effects were attributable to the increased activity of thermogenic adipocytes, as upregulated thermogenic markers in brown and inguinal adipose tissue and improved cold tolerance were induced by central FGF19. However, under blunted sympathetic activity, the described effects were abolished. Moreover, cold exposure induced upregulation of FGF19 receptors and coreceptors specifically in the hypothalamus, suggesting a critical metabolic adaptation for thermoregulation and energy homeostasis. Our findings indicate that central FGF19 signaling improves energy homeostasis in DIO mice, at least in part, by stimulating sympathetic activity and adipose tissue thermogenesis. These findings highlight FGF19's potential as a therapeutic target for obesity and metabolic disorders.NEW & NOTEWORTHY Although most studies associate central fibroblast growth factor 19 (FGF19) with reduced food intake, our findings highlight its role in enhancing thermogenesis in white and brown adipose tissues through sympathetic activation. Central FGF19 not only regulates feeding but also drives peripheral adaptations critical for energy homeostasis and body weight control under obesogenic conditions. These insights underscore the significance of top-down mechanisms in FGF19 action and its therapeutic potential for combating obesity.

Obesity is a global health challenge associated with significant metabolic and cardiovascular risks. Bariatric surgery and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are effective interventions for weight loss and metabolic improvement, yet their comparative effects on systemic metabolism-particularly energy metabolism, bone health, and heart function-remain unclear. In this study, obese male mice underwent vertical sleeve gastrectomy (VSG), 6 wk of GLP-1RA (semaglutide) treatment, or sham procedure with saline injection as controls. Dynamic changes in body weight, food intake, fat mass, lean mass, and bone mineral density were monitored. Energy metabolism was assessed using indirect calorimetry. Bone parameters and heart function were evaluated by microcomputed tomography or echocardiography, respectively. Compared with obese controls, VSG and semaglutide treatment comparably reduced body weight and improved glucose metabolism. However, VSG decreased energy expenditure, whereas both treatments similarly promoted lipid utilization. Semaglutide treatment increased ambulatory activity during nighttime. VSG led to significant bone loss, although 6 wk of semaglutide treatment had no significant effects on the skeleton. Cardiovascular outcomes also differed: VSG increased stroke volume without altering heart mass, whereas semaglutide reduced heart mass and transiently elevated heart rate. These findings underscore the importance of carefully weighing the benefits and potential risks of different weight loss treatments when addressing obesity and its systemic complications.NEW & NOTEWORTHY Comparative studies of surgical and pharmaceutical approaches to weight loss offer critical insights that can guide clinical decision-making for managing obesity. VSG and semaglutide exhibit comparable efficacy in promoting weight reduction and improving glucose metabolism. VSG reduces energy expenditure, whereas semaglutide increases animal activity during nighttime. VSG leads to significant bone loss, whereas semaglutide preserves bone mass independent of weight loss. VSG improves cardiac outcomes, whereas semaglutide transiently affects heart function.

Obesity induction in mice requires high-fat diet exposure. Although hepatic steatosis develops, progression to inflammation and fibrosis, as in humans, requires prolonged exposure and additional dietary factors. Immunosuppression at room temperature may slow this progression. We evaluated thermoneutrality's effect on metabolic dysfunction-associated steatohepatitis (MASH) development using a fibrosis-inducing MASH [Gubra-Amylin NASH (GAN)] diet. Mice were fed either a MASH or chow diet and housed at room temperature or thermoneutrality. MASH diet groups were euthanized monthly from 4 to 7 mo. Serum markers of hepatic function were analyzed, and liver histology assessed steatosis, inflammation, ballooning [nonalcoholic fatty liver disease activity score (NAS) score], and fibrosis via Picrosirius Red staining. MASH diet increased body weight, liver-to-body mass ratio, and hepatic fat, with no difference between housing conditions. Housing temperature had minimal effects on MASH. Serum markers and hepatic fibrosis were similar across groups. NAS score was lower at 4 mo in thermoneutral MASH mice but not by 7 mo. Thermoneutrality did not significantly impact MASH development. These findings, alongside existing literature, suggest thermoneutral housing does not consistently enhance MASH progression in GAN MASH-fed mice.NEW & NOTEWORTHY The development of MASH in mice-does housing temperature make a real difference?

Gestational diabetes mellitus (GDM) represents a major public health concern due to adverse maternal postpartum and long-term outcomes. Current strategies to manage GDM fail to reduce the maternal risk to develop later impaired glucose tolerance (IGT) and type 2 diabetes (T2D). In a rodent model of diet-induced GDM without obesity, we explored the perinatal metabolic adaptations in dams with gestational IGT followed by either persistent or resolved postpartum IGT. Female Sprague-Dawley rats were fed a high-fat high-sucrose (HFHS) or a chow [control group (CTL)] diet, 1 wk before mating and throughout gestation (G). Following parturition, HFHS dams were randomized to two subgroups: one switched to a chow diet and the other one maintained on an HFHS diet throughout lactation (L). Oral glucose tolerance tests (OGTTs) were performed, and plasma metabolome-lipidome were characterized at G12 and L12. We found that 1) in GDM-pregnant dams, IGT was associated with incomplete fatty acid oxidation (FAO), enhanced gluconeogenesis, altered insulin signaling, and oxidative stress; 2) improved glucose tolerance postpartum seemed to restore complete FAO along with elevation of nervonic acid-containing sphingomyelins, assumed to impart β-cell protection; and 3) persistence of IGT after delivery was associated with metabolites known to predict the early onset of insulin and leptin resistance, with maintained liver dysfunction. Our findings shed light on the impact of postpartum IGT evolution on maternal metabolic outcome after an episode of GDM. They suggest innovative strategies, implemented shortly after delivery and targeted on these biomarkers, should be explored to curb or delay the transition from GDM to T2D in these mothers.NEW & NOTEWORTHY Specific metabolomic/lipidomic features are associated with GDM postpartum outcomes. GDM-pregnant dams exhibit partial fatty acid oxidation and boosted gluconeogenesis. Resolution of postpartum IGT relies on nervonic acid-sphingomyelin, a β-cell protector. Postpartum IGT persistence suggests muscle insulin resistance and liver dysfunction.