BACKGROUND Insulin resistance of the brain can unfavorably affect long-term weight maintenance and body fat distribution. Little is known if and how brain insulin sensitivity can be restored in humans. We aimed to evaluate the effects of an exercise intervention on insulin sensitivity of the brain and how this relates to exercise-induced changes in whole-body metabolism and behavior.METHODS In this clinical trial, sedentary participants who were overweight and obese underwent an 8-week supervised aerobic training intervention. Brain insulin sensitivity was assessed in 21 participants (14 women, 7 men; age range 21–59 years; BMI range 27.5–45.5 kg/m2) using functional MRI, combined with intranasal administration of insulin, before and after the intervention.RESULTS The exercise program resulted in enhanced brain insulin action to the level of a person of healthy weight, demonstrated by increased insulin-induced striatal activity and strengthened hippocampal functional connectivity. Improved brain insulin action correlated with increased mitochondrial respiration in skeletal muscle, reductions in visceral fat and hunger, as well as improved cognition. Mediation analyses suggest that improved brain insulin responsiveness helps mediate the peripheral exercise effects leading to healthier body fat distribution and reduced perception of hunger.CONCLUSION Our study demonstrates that an 8-week exercise intervention in sedentary individuals can restore insulin action in the brain. Hence, the ameliorating benefits of exercise toward brain insulin resistance may provide an objective therapeutic target in humans in the challenge to reduce diabetes risk factors.TRIAL REGISTRATION ClinicalTrials.gov (NCT03151590).FUNDING BMBF/DZD 01GI0925.
Stephanie Kullmann, Thomas Goj, Ralf Veit, Louise Fritsche, Lore Wagner, Patrick Schneeweiss, Miriam Hoene, Christoph Hoffmann, Jürgen Machann, Andreas Niess, Hubert Preissl, Andreas L. Birkenfeld, Andreas Peter, Hans-Ulrich Häring, Andreas Fritsche, Anja Moller, Cora Weigert, Martin Heni
Obesity-induced asthma responds poorly to all current pharmacological interventions, including steroids; suggesting that classic, eosinophilic inflammation is not a mechanism. As insulin resistance and hyperinsulinemia are common in obese individuals and associated with increased risk of asthma, we used diet-induced obese mice to study how insulin induces airway hyperreactivity. Inhaled 5-HT or methacholine induced dose dependent bronchoconstriction that was significantly potentiated in obese mice. Cutting the vagus nerves eliminated bronchoconstriction in both obese and non-obese animals indicating it was mediated by a neural reflex. There was significantly greater density of airway sensory nerves in obese than in non-obese mice. Deleting insulin receptors on sensory nerves prevented the increase in sensory nerve density and prevented airway hyperreactivity in obese mice with hyperinsulinemia. Our data demonstrate that high levels of insulin drives obesity-induced airway hyperreactivity by increasing sensory innervation of the lung. Therefore, pharmacological interventions to control metabolic syndrome and limit reflex-mediated bronchoconstriction may be a more effective approach to reduce asthma exacerbations in obese and asthmatic patients.
Gina N. Calco, Jessica N. Maung, David B. Jacoby, Allison D. Fryer, Zhenying Nie
Puberty is associated with transient insulin resistance that normally recedes at the end of puberty; however, in overweight children insulin resistance persists leading to an increased risk of type 2 diabetes. The mechanisms whereby pancreatic β cells adapt to pubertal insulin resistance, and how they are affected by the metabolic status, have not been investigated. Here we show that puberty is associated with a transient increase in β-cell proliferation in rats and humans of both sexes. In rats, β-cell proliferation correlated with a rise in growth hormone (GH) levels. Serum from pubertal rats and humans promoted β-cell proliferation, suggesting the implication of a circulating factor. In pubertal rat islets, expression of genes of the GH/serotonin (5-HT) pathway underwent changes consistent with proliferative effect. Inhibition of the pro-proliferative 5-HT receptor isoform HTR2B blocked the increase in β-cell proliferation in pubertal islets ex vivo and in vivo. Peri-pubertal metabolic stress blunted β-cell proliferation during puberty and led to altered glucose homeostasis later in life. This study identifies a role of GH/GHR/5-HT/HTR2B signaling in the control of β-cell mass expansion during puberty and a mechanistic link between pubertal obesity and the risk of developing type 2 diabetes.
Anne-Laure Castell, Clara Goubault, Mélanie Ethier, Grace Fergusson, Caroline Tremblay, Marie Baltz, Dorothée Dal Soglio, Julien Ghislain, Vincent Poitout
BACKGROUND. Apolipoprotein CIII is a regulator of triglyceride (TG) metabolism, and due to its association with risk of cardiovascular disease, is an emergent target for pharmacological intervention. The impact of substantially lowering apoC-III on lipoprotein metabolism is not clear. METHODS. We investigated the kinetics of apolipoproteins B48 and B100 in chylomicrons, VLDL1, VLDL2, IDL and LDL in subjects heterozygous for a loss-of-function (LOF) mutation in the APOC3 gene. Studies were conducted in the post-prandial state to provide a more comprehensive view of the influence of this protein on TG transport. RESULTS. Compared to non-LOF subjects, a genetically-determined decrease in apoC-III resulted in marked acceleration of lipolysis of triglyceride-rich lipoproteins (TRL), increased removal of VLDL remnants from the bloodstream, and a substantial decrease in circulating levels of VLDL1, VLDL2 and IDL particles. Production rates for apolipoprotein B48-containing chylomicrons and apoB100-containing VLDL1 and VLDL2 were not different between LOF carriers and non-carriers. Likewise, the rate of production of LDL was not affected by the lower apoC-III level, nor was the concentration of LDL-apoB100 or its clearance rate. CONCLUSION. These findings indicate that apoC-III lowering will have a marked effect on TRL and remnant metabolism, with possibly significant consequences for cardiovascular disease prevention. TRIAL REGISTRATIONS. Clinical Trials NCT04209816 and NCT01445730 FUNDING. This project was funded by grants from Swedish Heart-Lung Foundation, Swedish Research Council, ALF grant from the Sahlgrenska University Hospital, Novo Nordisk Foundation, Sigrid Juselius Foundation, Helsinki University Hospital Government Research funds, Finnish Heart Foundation, and Finnish Diabetes Research Foundation.
Marja-Riitta Taskinen, Elias Björnson, Niina Matikainen, Sanni Söderlund, Joel Rämo, Mari-Mia Ainola, Antti Hakkarainen, Carina Sihlbom, Annika Thorsell, Linda Andersson, Per-Olof Bergh, Marcus Henricsson, Stefano Romeo, Martin Adiels, Samuli Ripatti, Markku Laakso, Chris J. Packard, Jan Borén
Obesity is an important risk factor for atrial fibrillation (AF), but a better mechanistic understanding of obesity-related atrial fibrillation is required. Serum glucocorticoid kinase 1 (SGK1) is a kinase positioned within multiple obesity-related pathways, and prior work has shown a pathologic role of SGK1 signaling in ventricular arrhythmias. We validated a mouse model of obesity-related AF using wild type mice fed a high fat diet. RNA sequencing of atrial tissue demonstrated substantial differences in gene expression, with enrichment of multiple SGK1-related pathways, and we confirmed upregulated of SGK1 transcription, activation, and signaling in obese atria. Mice expressing a cardiac specific dominant negative SGK1 were protected from obesity-related AF, through effects on atrial electrophysiology, action potential characteristics, structural remodeling, inflammation, and sodium current. Overall, this study demonstrates the promise of targeting SGK1 in a mouse model of obesity-related AF.
Aneesh Bapat, Guoping Li, Ling Xiao, Ashish Yeri, Maarten Hulsmans, Jana Grune, Masahiro Yamazoe, Maximillian J. Schloss, Yoshiko Iwamoto, Justin G. Tedeschi, Xinyu Yang, Matthias Nahrendorf, Anthony Rosenzweig, Patrick T. Ellinor, Saumya Das, David Milan
Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR wild-type NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC with significant enrichment of the cholesterol gene signature, indicating targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and also drastically reverse immuno-cold to an inflamed phenotype in vivo which exhibited a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin. These findings could provide a innovative clinical insight to treat NSCLC patients with immuno-cold tumors.
Wenjun Mao, Yun Cai, Danrong Chen, Guanyu Jiang, Yongrui Xu, Ruo Chen, Fengxu Wang, Xuehai Wang, Mingfeng Zheng, Xinyuan Zhao, Jie Mei
Genetic polymorphisms are associated with the development of nonalcoholic fatty liver disease (NAFLD). Semaphorin7a (Sema7a) deficiency in mouse peritoneal macrophages reduces fatty acid (FA) oxidation. Here, we identified 17 individuals with SEMA7A heterozygous mutations in 470 patients with biopsy-proven NAFLD. SEMA7A heterozygous mutations increased susceptibility to NAFLD, steatosis severity, and NAFLD activity scores in humans and mice. The Sema7aR145W mutation (equivalent to human SEMA7AR148W) significantly induced small lipid droplet accumulation in mouse livers compared with WT mouse livers. Mechanistically, the Sema7aR145W mutation increased N-glycosylated Sema7a and its receptor integrin β1 proteins in the cell membranes of hepatocytes. Furthermore, Sema7aR145W mutation enhanced its protein interaction with integrin β1 and PKC-α and increased PKC-α phosphorylation, which were both abrogated by integrin β1 silencing. Induction of PKCα_WT, but not PKCα_dominant negative, overexpression induced transcriptional factors Srebp1, Chrebp, and Lxr expression and their downstream Acc1, Fasn, and Cd36 expression in primary mouse hepatocytes. Collectively, our findings demonstrate that the SEMA7AR148W mutation is a potentially new strong genetic determinant of NAFLD and promotes intrahepatic lipid accumulation and NAFLD in mice by enhancing PKC-α–stimulated FA and triglyceride synthesis and FA uptake. The inhibition of hepatic PKC-α signaling may lead to novel NAFLD therapies.
Nan Zhao, Xiaoxun Zhang, Jingjing Ding, Qiong Pan, Ming-Hua Zheng, Wen-Yue Liu, Gang Luo, Jiaquan Qu, Mingqiao Li, Ling Li, Ying Cheng, Ying Peng, Qiaoling Xie, Qinglin Wei, Qiao Li, Lingyun Zou, Xinshou Ouyang, Shi-Ying Cai, James L. Boyer, Jin Chai
Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the non-canonical IκB kinases TBK1 and IKKε with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human subjects. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet (WD)-fed Ldlr-/- mice, and protects against atherogenesis. Amlexanox ameliorates dyslipidemia, inflammation and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrates an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuates monocytosis, eosinophilia and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a new therapy for hypercholesterolemia and atherosclerosis.
Peng Zhao, Xiaoli Sun, Zhongji Liao, Hong Yu, Dan Li, Zeyang Shen, Christopher K. Glass, Joseph L. Witztum, Alan R. Saltiel
Pathogenic variants in the human F Box and Leucine Rich Repeat Protein 4 (FBXL4) gene result in an autosomal recessive, multi-systemic, mitochondrial disorder involving variable mitochondrial depletion and respiratory chain (RC) complex deficiencies with lactic acidemia. As no FDA-approved effective therapies exist, we sought to characterize translational C. elegans and zebrafish animal models, as well as human fibroblasts, to study FBXL4-/- disease mechanisms and identify preclinical therapeutic leads. Developmental delay, impaired fecundity and neurologic and/or muscular activity, mitochondrial dysfunction, and altered lactate metabolism were identified in fbxl-1(ok3741) C. elegans. Detailed studies of a pyruvate dehydrogenase complex activator, dichloroacetate (DCA) in fbxl-1(ok3741) C. elegans demonstrated its beneficial effects on fecundity, neuromotor activity, and mitochondrial function. Validation studies were performed in fbxl4sa12470 zebrafish larvae and in FBXL4-/- human fibroblasts, which showed DCA efficacy in preventing brain damage, impairment of neurologic and/or muscular function, mitochondrial biochemical dysfunction, and stress-induced morphologic and ultrastructural mitochondrial defects. These data demonstrate that fbxl-1 (ok3741) C. elegans and fbxl4sa12470 zebrafish provide robust translational models to study mechanisms and identify preclinical therapeutic candidates for FBXL4-/- disease. Further, DCA is a lead therapeutic candidate with therapeutic benefit on diverse aspects of survival, neurologic and/or muscular function, and mitochondrial physiology that warrants rigorous clinical trial study in human subjects with FBXL4-/- disease.
Manuela Lavorato, Eiko Nakamaru-Ogiso, Neal D. Mathew, Elizabeth Herman, Nina K. Shah, Suraiya Haroon, Rui Xiao, Christoph Seiler, Marni J. Falk
Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). We aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-ketoacids (BCKAs) and hepatic BCKDK expression are associated with the presence and severity of non-alcoholic fatty liver disease (NAFLD). Eighty metabolites (3 BCKA, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 bariatric surgery patients with severe obesity (BMI > 35 kg/m2) with scored liver biopsy samples. Metabolite principal component analysis (PCA) factors, BCKA, branched-chain amino acids (BCAA), and the BCKA:BCAA ratio were tested for associations with steatosis grade and presence of non-alcoholic steatohepatitis (NASH). Of all analytes tested, only the valine-derived BCKA, α-ketoisovalerate, and the BCKA:BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from two independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowers BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.
Thomas Grenier-Larouche, Lydia Coulter Kwee, Yann Deleye, Paola Leon-Mimila, Jacquelyn M. Walejko, Robert W. McGarrah, Simon Marceau, Sylvain Trahan, Christine Racine, André C. Carpentier, Aldons J. Lusis, Olga Ilkayeva, Marie-Claude Vohl, Adriana Huertas-Vazquez, Andre Tchernof, Svati H. Shah, Christopher B. Newgard, Phillip J. White
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