American journal of physiology. Endocrinology and metabolism最新文献

{"title":"CEFIP deficiency in mice enhances glucose tolerance despite compromised muscle function.","authors":"Mazvita R Nyasha, Juri Tachikawa, Hikaru Komatsuzaki, Weijian Chen, Maya Onodera, Daiki Kojima, Fukie Yaoita, Makoto Kanzaki","doi":"10.1152/ajpendo.00302.2024","DOIUrl":"10.1152/ajpendo.00302.2024","url":null,"abstract":"<p><p>Mechanotransduction in skeletal muscles is crucial for promoting global physical performance by coordinating muscular strength and metabolic properties, yet the underlying mechanisms and key regulatory molecules remain poorly understood. We identified cardiac-enriched FHL2-interacting protein (CEFIP), a <i>Z</i>-disc localized protein upregulated upon contractility acquisition, as a potential integrator maintaining the balance between muscular performance and glucose metabolism. CEFIP deficiency resulted in decreased physical fitness, including lower running capabilities and weaker grip strength, even with no apparent myofiber disorganization. At the molecular level, CEFIP-deficient mice exhibited dampened expression of striated muscle activator of Rho signaling (<i>STARS</i>), a key mechanosensitive factor, whereas four-and-a-half LIM domain (<i>FHL</i>)<i>1</i> and <i>FHL3</i> were upregulated, with <i>FHL1</i> expression further increasing in response to exercise. Despite the overall compromised physical performance, CEFIP-deficient mice unexpectedly showed enhanced insulin responsiveness and increased muscular AMPK phosphorylation. Moreover, CEFIP-deficient mice exhibited heightened susceptibility to an exercise load, as evidenced by PGC-1α upregulation and augmented GLUT4 regulation, and enhanced insulin sensitivity, as indicated by sarcolemmal GLUT4 translocation. Taken together, our findings suggest that CEFIP serves as a key regulatory link between exercise performance and metabolic properties, potentially through Z-disc-mediated mechanosensitive processes in exercising skeletal muscles.<b>NEW & NOTEWORTHY</b> The authors identified CEFIP as a regulator linking exercise performance and metabolism, potentially through Z-disc-mediated mechanosensitive processes. CEFIP-deficient mice exhibited enhanced exercise-induced insulin response but impaired physical fitness, highlighting its complex role in balancing insulin sensitivity, glucose homeostasis, and muscle function. These findings underscore the necessity of proper CEFIP regulation for physiological homeostasis, though its precise role in wild-type mice remains unclear and warrants further investigation.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E1021-E1040"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP1A1/1A2 enzymes mediate glucose homeostasis and insulin secretion in mice in a sex-specific manner.","authors":"Ma Enrica Angela Ching, Myriam P Hoyeck, Lahari Basu, Rayanna Merhi, Emilia Poleo-Giordani, Erin van Zyl, Angela M Crawley, Jennifer E Bruin","doi":"10.1152/ajpendo.00284.2024","DOIUrl":"10.1152/ajpendo.00284.2024","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that controls the expression of several downstream targets including xenobiotic metabolism enzymes, cytochrome P450 1A1 and 1A2 (<i>Cyp1a1/1a2</i>). Besides xenobiotic metabolism, AhR also mediates responses to other stressors including high-fat diets (HFDs). Although global deletion or downregulation of AhR protects against metabolic dysfunction in HFD-fed mice, the role of <i>Cyp1a1/1a2</i> in glucose homeostasis remains unclear. We demonstrated that <i>Cyp1a1</i> expression is induced in mouse pancreatic islets not only by xenobiotic exposure but also by HFD feeding. Since CYP1A1/1A2 enzymes can produce reactive oxygen intermediates, we hypothesized that chronic CYP1A1/1A2 activation may contribute to HFD-induced metabolic dysfunction in mice, and thus, deleting these enzymes may be protective. We fed 29- to 31-wk-old male and female global <i>Cyp1a1/1a2</i> knockout (<i>Cyp</i>^KO) and wild-type (<i>Cyp</i>^WT) mice a 45% HFD or standard chow for 14 wk. <i>Cyp</i>^KO females were partially protected from HFD-induced glucose intolerance, and chow-fed <i>Cyp</i>^KO females had lower plasma insulin and suppressed insulin secretion in isolated islets compared with <i>Cyp</i>^WT females. Meanwhile, <i>Cyp</i>^KO males exhibited HFD-induced hyperinsulinemia later than <i>Cyp</i>^WT males. HFD feeding elevated <i>Cyp1a1</i> and other stress genes in <i>Cyp</i>^WT male islets but not in <i>Cyp</i>^KO islets, indicating that CYP1A1 mediates islet stress responses. Liver pathology, adiposity, and adipose inflammation were primarily affected by diet, not genotype, in both sexes. Our study highlights a novel sex-dependent role for <i>Cyp1a1/1a2</i> in shaping the systemic metabolic response to HFD feeding, suggesting that CYP1A1/1A2 enzymes are involved in glucose homeostasis, insulin secretion, and islet stress responses.<b>NEW & NOTEWORTHY</b> Cytochrome P450 (CYP)1A1/1A2 enzymes have sex-specific roles in glucose homeostasis in mice. In females, global <i>Cyp1a1/1a2</i> deletion partially protects from glucose intolerance in high-fat diet (HFD)-fed mice and lowers plasma insulin in chow-fed mice. In males, <i>Cyp1a1/1a2</i> deletion delays HFD-induced hyperinsulinemia in vivo and inhibits HFD-induced islet stress responses. Genotype-driven differences were only seen in islets, suggesting a novel role for islet CYP1A1/1A2 enzymes in responding to metabolic stress.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E885-E898"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum for Waterman et al., volume 327, 2024, p. E655-E667.","authors":"","doi":"10.1152/ajpendo.00170.2024_COR","DOIUrl":"https://doi.org/10.1152/ajpendo.00170.2024_COR","url":null,"abstract":"","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 6","pages":"E1052"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bile acid regulation of xenobiotic nuclear receptors on the expressions of orosomucoids in the liver.","authors":"Ji Ho Suh, Inyoung Cheon, Hyun-Jung Jung, Sung Ho Lee, Mi Jeong Heo, Matthew DeBerge, Clavia Ruth Wooton-Kee, Kang Ho Kim","doi":"10.1152/ajpendo.00417.2024","DOIUrl":"10.1152/ajpendo.00417.2024","url":null,"abstract":"<p><p>The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic nuclear receptors activated by various xenobiotics, drugs, hormones, and bile acids (BAs). Upon activation, these nuclear receptors play critical roles in regulating systemic energy homeostasis. However, precise mechanisms through which CAR and PXR influence systemic metabolism remain incompletely understood. Here, we investigated the impact of CAR and PXR on the liver-secreted hormone (i.e., hepatokine) expressions in response to BA stress, such as cholic acid (CA) feeding. Our analysis revealed that several BA-activated genes, including the well-known CAR/PXR target, aldo-keto reductase family 1, member B7 (<i>Akr1b7</i>), were commonly increased by CAR- and PXR-agonist treatments. Notably, we identified a gene cluster encoding new BA-regulated hepatokines, orosomucoids (ORMs), as direct transcriptional targets of CAR and PXR. The <i>Orm1</i> and <i>Orm2</i> expressions were completely abolished in the absence of both CAR and PXR following CA feeding. In addition, we found that <i>Orm</i> transcriptions are dynamically regulated under various metabolic conditions, proposing a potential contribution of CAR/PXR. In conclusion, our study demonstrated that BA stress activates CAR and PXR, which play a key role in regulating hepatokine expression, including ORMs. This suggests a potential link between hepatic BA signaling, CAR/PXR activity, and systemic metabolic effects.<b>NEW & NOTEWORTHY</b> Hepatic bile acid signaling plays a crucial role in coordinating systemic metabolism between the liver and other peripheral tissues. Our report demonstrates that, under bile acid-enriched conditions, activation of nuclear receptors CAR and PXR stimulate the expression of several putative hepatokines, including the orosomucoid gene family, which may exert regulatory effects in the liver and adipose tissue against metabolic disorders.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E940-E951"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12158448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of reducing sedentary behavior on liver insulin sensitivity, liver fat content, and liver enzyme levels: a six-month randomized controlled trial.","authors":"Saara Laine, Tanja Sjöros, Taru Garthwaite, Miikka-Juhani Honka, Eliisa Löyttyniemi, Jooa Norha, Olli Eskola, Mikko Koivumäki, Henri Vähä-Ypyä, Harri Sievänen, Tommi Vasankari, Jussi Hirvonen, Kirsi Laitinen, Noora Houttu, Kari K Kalliokoski, Virva Saunavaara, Juhani Knuuti, Ilkka H A Heinonen","doi":"10.1152/ajpendo.00446.2024","DOIUrl":"10.1152/ajpendo.00446.2024","url":null,"abstract":"<p><p>Metabolic syndrome increases the risk of developing noncommunicable diseases such as metabolic dysfunction-associated steatotic liver disease. The aim was to investigate the effects of sedentary behavior (SB) reduction on liver glucose uptake (LGU), endogenous glucose production (EGP), liver fat content (LFC), and liver enzyme levels [alanine aminotransferase (ALT), aspartate aminotransferase, and γ-glutamyltransferase]. Forty-four sedentary (daily SB time ≥ 10 h), physically inactive middle-aged adults with metabolic syndrome were randomized into intervention (INT; <i>n</i> = 23, 21 completed) and control (CON; <i>n</i> = 21, 19 completed) groups. For 6 mo, INT aimed to limit SB by 1 h/day, whereas CON aimed to maintain usual habits. SB and physical activity (PA) were measured continuously with hip-worn accelerometers. Before and at the end of the intervention, LGU was measured using positron emission tomography during the hyperinsulinemic-euglycemic clamp. EGP was calculated, and LFC was measured by magnetic resonance spectroscopy. INT reduced SB by 51 [95% confidence interval (CI): 22, 78] min/day and increased moderate-to-vigorous physical activity (MVPA) by 22 (95% CI: 12, 33) min/day, with no significant change in CON. Differences in liver health markers between the groups were not significant. However, according to the exploratory analyses among participants who successfully reduced SB, ALT decreased (-1.1 [95% CI: 0.93, 1.36] U/L) compared with the continuously sedentary participants (+0.8 [95% CI: 0.65, 1.05] U/L) (group × time, <i>P</i> = 0.006). To enhance liver health, reducing SB for longer durations and/or increasing the intensity of PA may be necessary. However, successfully reducing SB may lead to better levels of circulating ALT liver enzymes.<b>NEW & NOTEWORTHY</b> Aiming to reduce sedentary behavior (SB) by 1 h/day did not significantly influence liver health markers, suggesting that more substantial reductions or a different approach might be necessary to see improvements. However, achieving the desired behavioral change could lead to improvements in ALT levels. This study is the first to analyze how reducing SB and replacing it with nonguided physical activity impacts liver health in adults with metabolic syndrome, offering insights for future intervention strategies.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 6","pages":"E756-E771"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic effect of combined functional overload and endurance-type swimming exercise on whole body metabolism in mice.","authors":"Takanaga Shirai, Kazuki Uemichi, Ryoto Iwai, Hayato Shinkai, Tomohiro Iwata, Riku Tanimura, Shunsuke Sugiyama, Tohru Takemasa","doi":"10.1152/ajpendo.00433.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00433.2024","url":null,"abstract":"<p><p>In this study, we examined the effects of concurrent functional overload and endurance exercise on muscle hypertrophy, mitochondrial function, and systemic adaptations in male mice. The mice were assigned to three groups: Sham (Sham), overload-induced hypertrophy (OL), and overload with concurrent 60-min free swimming (5 times/wk) (OL + Swim), for 4 wk. Although OL promoted muscle hypertrophy and protein synthesis through the Akt/mammalian/mechanistic target of rapamycin (mTOR) signaling pathway, the addition of swimming (OL + Swim) attenuated these effects, resulting in less pronounced muscle growth and a smaller increase in myofiber cross-sectional area. Notably, the OL + Swim group exhibited enhanced mitochondrial activity and glycogen content compared with the OL group. Both the OL and OL + Swim groups showed elevated rates of protein synthesis, with a significant upregulation of AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the OL + Swim group, suggesting enhanced mitochondrial biogenesis and adaptation. Concurrent training also resulted in systemic benefits, including reduced inguinal and epididymal white adipocyte size, improved mitochondrial enzyme activities in adipose and liver tissues, and higher levels of fibronectin type III domain containing protein 5 (FNDC5), fibroblast growth factor 21 (FGF21), and brain-derived neurotrophic factor (BDNF) in serum, which contributed to enhanced muscle protein synthesis in cultured muscle cells. These results highlight the trade-offs between muscle hypertrophy and metabolic health in mice and underscore the importance of balanced training regimens to optimize overall metabolic health and muscle function. Our results provide further insight into how concurrent strength and endurance training can be optimized for health and performance benefits.<b>NEW & NOTEWORTHY</b> This study provides novel insights into the mechanisms underlying the interference effect that occurs in concurrent training, highlighting the potential systemic benefits of combining resistance and endurance exercises. Despite a reduction in muscle hypertrophy, concurrent training enhances metabolic adaptations and systemic health markers and offers a comprehensive approach to improving both muscle and metabolic fitness.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 5","pages":"E695-E710"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLP-1 receptor agonist exendin-4 suppresses food intake by inhibiting hindbrain orexigenic NPY neurons.","authors":"Jiayi Shen, Mengtian Wang, Guodong Pang, Yan Zhang, Jian Zhang, Yuyan Shi, Ji Liu, Cheng Zhan","doi":"10.1152/ajpendo.00528.2024","DOIUrl":"10.1152/ajpendo.00528.2024","url":null,"abstract":"<p><p>Peripherally delivered glucagon-like peptide-1 (GLP-1)-based drugs suppress eating through their action in the brain. However, the specific neuronal mechanisms, especially their impacts on the orexigenic circuit, remain largely elusive. Neuropeptide Y (NPY) neurons in the nucleus tractus solitarius (NTS) are newly identified as orexigenic neurons with a potent eating-stimulating effect, but their responses to GLP-1 drugs are unknown. Through ex vivo electrophysiological recordings, we study the impacts of GLP-1 receptor (GLP-1R) agonist exendin-4 on NTS^NPY neurons. We discovered that the GLP-1R agonist exendin-4 inhibits NTS^NPY neuronal activity via GABA_b receptors by augmenting presynaptic GABA release. We also explored the contribution of NTS^NPY neurons to exendin-4-mediated eating suppression. Interestingly, chemogenetic activation of NTS^NPY neurons effectively counteracted exendin-4-induced anorexigenic effect. Moreover, chemogenetic inhibition of NTS^NPY neurons mimicked the eating-suppressing effect of exendin-4. Collectively, our findings highlight a population of orexigenic NTS^NPY neurons that may be targeted by a GLP-1R agonist to suppress food intake, suggesting that this neuronal population has translational importance as a potential therapeutic target for obesity treatment.<b>NEW & NOTEWORTHY</b> This study discovers that the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 indirectly inhibits the majority of orexigenic hindbrain NPY neurons via GABA_b receptors by augmenting presynaptic GABA release. Chemogenetic activation of these NPY neurons effectively counteracts exendin-4 (Exn-4)-induced anorexigenic effect, whereas chemogenetic inhibition of them mimics the eating-suppressing effect of exendin-4. This study uncovers a mechanism by which Exn-4 inhibits orexigenic hindbrain NPY neurons, thereby providing new insights into how GLP-1 drugs suppress food intake.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E661-E674"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased cGMP improves microvascular exercise training adaptations in diet-induced obesity.","authors":"Nathan C Winn, David A Cappel, Ethan D Pollack, Louise Lantier, Jillian K Riveros, Deanna P Bracy, Joshua A Beckman, David H Wasserman","doi":"10.1152/ajpendo.00368.2024","DOIUrl":"10.1152/ajpendo.00368.2024","url":null,"abstract":"<p><p>With the development of atherosclerosis, impaired microvascular function can result in diminished capacity for ambulation and is a risk factor for type 2 diabetes. Dynamic changes in vascular tone are determined, in large part, by the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO)/cGMP axis. We used pharmacological gain of function of the eNOS/NO/cGMP axis in diet-induced obese (DIO) mice and reduced function in lean mice to test the hypothesis that functionality of this vascular control mechanism parallels the benefits of an exercise training regimen. DIO mice have 50% lower exercise capacity (<i>P</i> < 0.0001) than lean mice and were used for pharmacological gain of function. The phosphodiesterase-5a (PDE-5a) inhibitor, sildenafil, increases cGMP and was administered to DIO mice daily. In sedentary mice, neither acute nor chronic sildenafil improves exercise capacity. In contrast, chronic sildenafil synergizes with exercise training to improve performance during an incremental exercise test. Improved exercise performance was accompanied by a 40% increase in basal skeletal muscle capillary flow velocity and <i>∼</i>20% increase in plasma-perfused capillary density measured via intravital microscopy. Loss of function was tested in lean mice hemizygous for endothelial cell (EC) specific eNOS creating an EC-eNOS knockdown (KD). EC-eNOS KD decreases capillary density and exercise tolerance in sedentary mice; however, it did not prevent exercise-training-induced improvements in endurance capacity. These data show that <i>1</i>) increasing cGMP with sildenafil enhances microcirculatory function and exercise work tolerance that results from training; <i>2</i>) eNOS KD does not prevent the microcirculatory or improvements in exercise tolerance with training. PDE-5a inhibitors combined with physical exercise are a potential mechanism for improving ambulation in patients with circulatory limitations.<b>NEW & NOTEWORTHY</b> This study used pharmacological gain-of-function and genetic loss-of-function approaches to test the hypothesis that the eNOS/NO/cGMP axis is central to exercise training adaptations in microcirculatory function and exercise capacity. Chronic but not acute treatment with the PDE5 inhibitor, sildenafil, synergizes with exercise training to improve performance with incremental exercise in obese mice; whereas endothelium-specific knockdown in eNOS does not blunt the microcirculatory adaptations and improvements in exercise tolerance with training.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 5","pages":"E711-E722"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The choice of diet is determinative for the manifestation of UCP1-dependent diet-induced thermogenesis.","authors":"Raman Ahluwalia, Ineke H N Luijten, Celso P B Sousa-Filho, G Ruda F Braz, Natasa Petrovic, Irina G Shabalina, Barbara Cannon, Jan Nedergaard","doi":"10.1152/ajpendo.00038.2025","DOIUrl":"10.1152/ajpendo.00038.2025","url":null,"abstract":"<p><p>The existence of the phenomenon of diet-induced thermogenesis-and its possible mediation by UCP1 in brown adipose tissue-has long been, and is presently, an important metabolic controversy. Particularly, several recent studies have failed to observe the hallmark of the phenomenon: augmentation of diet-induced obesity (i.e., fat mass) in UCP1-ablated mice, thus further casting doubt on the possible importance of this thermogenesis, for example in human metabolic control. However, scrutiny of the experimental details revealed important procedural differences between experiments that did not show or did show this augmentation of diet-induced obesity. Particularly, there were notable differences between the commercial diets used (Research Diets or Ssniff). We, therefore, tested to what degree these differences would suffice to explain the absence of a UCP1 effect. Wild-type mice fed Research Diets high-fat diet became obese, but UCP1-ablated mice became even more obese, as expected if UCP1-dependent diet-induced thermogenesis exists. Mice fed the Ssniff high-fat diet became less obese than those on the Research Diets food-and, importantly, no effect of UCP1 ablation was seen. The result with the Research Diets diet was fully due to differences in total fat mass and not explainable by differences in food intake. The two diets are different in carbohydrate (sucrose) and lipid (lard vs. palm oil) composition and in texture and taste. Probably some of these factors explain the difference, but the important conclusion is that when an appropriate diet was offered, the body weight manifestation of the phenomenon of UCP1-dependent diet-induced thermogenesis was a reproducible phenomenon, the existence of which may have significance also for human metabolic control.<b>NEW & NOTEWORTHY</b> A main reason for the present interest in brown adipose tissue in humans is the possibility that this tissue mediates diet-induced thermogenesis, i.e., the ability to combust some of the foods eaten, thus lessening the burden of obesity. However, several recent papers have queried the existence of diet-induced thermogenesis. We demonstrate that these negative observations are explainable by the types of diet offered, and diet-induced thermogenesis thus remains a potentially important contributor to metabolic equilibrium.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E653-E660"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central lipid sensing pathways contribute to the control of puberty and its alterations in conditions of obesity.","authors":"Elvira Rodríguez-Vázquez, Álvaro Aranda-Torrecillas, María López-Sancho, Manuel Jiménez-Puyer, Silvia Daza-Dueñas, Alexia Barroso, Verónica Sobrino, Francisco Gaytan, Elia Obis, Juan M Castellano, Manuel Tena-Sempere","doi":"10.1152/ajpendo.00493.2024","DOIUrl":"10.1152/ajpendo.00493.2024","url":null,"abstract":"<p><p>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 (PPARs), and the bile-acid (BA) receptor, Takeda G protein-coupled receptor 5 (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 glycerolphospholipids, during the juvenile-pubertal transition and conditions of overweight linked to precocious puberty in female rats. Hypothalamic expression of the FFAR, <i>Gpr84</i>, as well as <i>Ppar-γ</i> and <i>Tgr5</i> gradually increased during the infantile-prepubertal transition, whereas early overfeeding increased hypothalamic mRNA levels of the FFARs, <i>Gpr43</i>, and <i>Gpr84</i>. Expression of <i>Gpr84</i>, <i>Ppar-α</i>, and <i>Tgr5</i> 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, whereas in early overfed rats, central stimulation of TGR5 signaling partially prevented obesity-induced advanced puberty; effects that were also marginally observed 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.<b>NEW & NOTEWORTHY</b> Puberty is highly sensitive to body energy status, and child obesity is often linked to perturbed puberty. However, whether this comes from excessive energy stores or specific nutrient signals altered in obesity remains largely unexplored. Using suitable preclinical models of early obesity and accelerated puberty, we disclose herein conclusive evidence for altered hypothalamic lipid profiles and the roles of specific lipid-sensing pathways in pubertal control, with a variable contribution depending on the maturational and nutritional status.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E675-E694"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}