Metabolism
Abstract
BACKGROUND. Adipose tissue-derived endotrophin, a peptide cleaved from the α3 chain of collagen VI during fibrogenesis, causes systemic insulin resistance in rodent models. Here, we evaluated the potential importance of endotrophin in regulating whole-body insulin sensitivity in people. METHODS. We evaluated: i) plasma endotrophin concentration, insulin sensitivity (assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled glucose tracer infusion) and adipose tissue expression of genes involved in endotrophin production in three groups of participants that were rigorously stratified by adiposity and insulin sensitivity [lean insulin-sensitive (Lean-IS; n=10), obese insulin-sensitive (Obese-IS; n=10), and obesity insulin-resistant (Obese-IR; n=10)]; ii) plasma endotrophin concentration and insulin sensitivity in 15 people with obesity and type 2 diabetes before and after marked (~18%) weight loss; and iii) the effect of endotrophin on insulin signaling (AKTser473 phosporylation) and insulin action (insulin-stimulated glucose uptake) in primary human skeletal muscle myotubes. RESULTS. Plasma endotrophin progressively increased from the Lean-IS to the Obese-IS to the Obese-IR group, was negatively associated with insulin sensitivity and positively associated with factors involved in adipose tissue endotrophin production, namely adipose tissue gene expression of matrix metalloproteinases and markers of hypoxia, inflammation, and fibrosis. Marked weight loss increased insulin sensitivity in conjunction with a decrease in plasma endotrophin concentration. Endotrophin inhibited insulin insulin-stimulated AKTser473 phosphorylation and insulin-stimulated glucose uptake in myotubes, which was restored by incubation with a neutralizing endotrophin antibody. CONCLUSIONS. These results suggest plasma endotrophin is both a biomarker and cause of whole-body insulin resistance in people with obesity.
Authors
Gordon I. Smith, Samuel Klein
Abstract
Bardet-Biedl Syndrome (BBS), a ciliopathy characterized by obesity, hyperphagia, and learning deficits, arises from mutations in BBS genes. More exacerbated symptoms occur with mutations in genes encoding the BBSome, a complex regulating primary cilia function. We investigated the mechanisms underlying BBS-induced obesity using a novel BBS5 knockout (BBS5-/-) mouse model. BBS5-/- mice displayed hyperphagia, learning deficits, glucose/insulin intolerance, and disrupted metabolic hormones, phenocopying human BBS. They displayed an unique immunophenotype in white adipose tissue with increased proinflammatory macrophages and dysfunctional regulatory T cells, suggesting a distinct mechanism for adiposity compared to typical obesity models. Additionally, BBS5-/- mice exhibited pancreatic islet hyperplasia but failed to normalize blood glucose, suggesting defective insulin action. Hypothalamic transcriptomics revealed dysregulated endocrine signaling pathways with functional analyses confirming defects in insulin, leptin, and cholecystokinin (CCK) signalling, while preserving glucagon-like peptide-1 receptor (GLP-1R) responsiveness. Notably, treatment with a GLP-1R agonist effectively alleviated hyperphagia, body weight gain, improved glucose tolerance, and circulating metabolic hormones in BBS5-/- mice. This study establishes BBS5-/- mice as a valuable translational model of BBS to understand the pathogenesis and develop novel treatments. Our findings highlight the therapeutic potential of GLP-1R agonists for managing BBS-associated metabolic dysregulation, warranting further investigation for clinical application.
Authors
Arashdeep Singh, Naila Haq, Mingxin Yang, Shelby Luckey, Samira Mansouri, Martha Campbell-Thompson, Lei Jin, Sofia Christou-Savina, Guillaume de Lartigue
Abstract
Hepatic insulin resistance is central to type 2 diabetes (T2D) and metabolic syndrome, but defining the molecular basis of this defect in humans is challenging because of limited tissue access. Utilizing inducible pluripotent stem cells differentiated into hepatocytes from control individuals and patients with T2D and liquid chromatography with tandem mass spectrometry–based (LC-MS/MS–based) phosphoproteomics analysis, we identified a large network of cell-intrinsic alterations in signaling in T2D. Over 300 phosphosites showed impaired or reduced insulin signaling, including losses in the classical insulin-stimulated PI3K/AKT cascade and their downstream targets. In addition, we identified over 500 phosphosites of emergent, i.e., new or enhanced, signaling. These occurred on proteins involved in the Rho-GTPase pathway, RNA metabolism, vesicle trafficking, and chromatin modification. Kinome analysis indicated that the impaired phosphorylation sites represented reduced actions of AKT2/3, PKCθ, CHK2, PHKG2, and/or STK32C kinases. By contrast, the emergent phosphorylation sites were predicted to be mediated by increased action of the Rho-associated kinases 1 and 2 (ROCK1/2), mammalian STE20-like protein kinase 4 (MST4), and/or branched-chain α-ketoacid dehydrogenase kinase (BCKDK). Inhibiting ROCK1/2 activity in T2D induced pluripotent stem cell–derived hepatocytes restored some of the alterations in insulin action. Thus, insulin resistance in the liver in T2D did not simply involve a loss of canonical insulin signaling but the also appearance of new phosphorylations representing a change in the balance of multiple kinases. Together, these led to altered insulin action in the liver and identified important targets for the therapy of hepatic insulin resistance.
Authors
Arijeet K. Gattu, Maria Tanzer, Tomer M. Yaron-Barir, Jared L. Johnson, Ashok Kumar Jayavelu, Hui Pan, Jonathan M. Dreyfuss, Lewis C. Cantley, Matthias Mann, C. Ronald Kahn
Abstract
Type 2 innate lymphoid cells (ILC2) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We employed cell systems and genetic models to examine the mechanism through which interleukin-13 (IL-13), an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drives beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPARγ-related pathways. The latter is mediated by increased expression and activity of PPARγ through IL-13 receptor α1 (IL-13Rα1) downstream effectors, STAT6 and p38 MAPK, respectively. Il13 knockout (Il13KO) or preadipocyte Il13ra1 knockout (Il13ra1KO) mice are refractory to cold- or β-3 adrenergic agonist-induced beiging in inguinal white adipose tissue, whereas Il4 knockout mice show no defects in beige adipogenesis. Il13KO and Il13ra1KO mouse models exhibit increased body weight/fat mass and dysregulated glucose metabolism but have a mild cold intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also find that genetic variants of human IL13RA1 are associated with body mass index and type 2 diabetes. These results suggest that IL-13 signaling-regulated beige adipocyte function may play a predominant role in modulating metabolic homeostasis rather than in thermoregulation.
Authors
Alexandra R. Yesian, Mayer M. Chalom, Nelson H. Knudsen, Alec L. Hyde, Jean Personnaz, Hyunjii Cho, Yae-Huei Liou, Kyle A. Starost, Chia-Wei Lee, Dong-Yan Tsai, Hsing-Wei Ho, Jr-Shiuan Lin, Jun Li, Frank B. Hu, Alexander S. Banks, Chih-Hao Lee
Abstract
Newborns exhibit a heightened vulnerability to inflammatory disorders due to their underdeveloped immune system, yet the underlying mechanisms remain poorly understood. Here we report that plasma spermidine is correlated with the maturity of human newborns and reduced risk of inflammation. Administration of spermidine led to the remission of neonatal inflammation in mice. Mechanistic studies revealed that spermidine enhanced the generation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via downstream eIF5A hypusination. Genetic deficiency or pharmacological inhibition of deoxyhypusine synthase (DHPS), a key enzyme of hypusinated eIF5A (eIF5AHyp), diminished the immunosuppressive activity of PMN-MDSCs, leading to aggravated neonatal inflammation. The eIF5AHyp pathway was found to enhance the immunosuppressive function via histone acetylation–mediated epigenetic transcription of immunosuppressive signatures in PMN-MDSCs. These findings demonstrate the spermidine-eIF5AHyp metabolic axis as a master switch to restrict neonatal inflammation.
Authors
Jiale Chen, Lin Zhu, Zhaohai Cui, Yuxin Zhang, Ran Jia, Dongmei Zhou, Bo Hu, Wei Zhong, Jin Xu, Lijuan Zhang, Pan Zhou, Wenyi Mi, Haitao Wang, Zhi Yao, Ying Yu, Qiang Liu, Jie Zhou
Meal-feeding promotes skeletal growth by ghrelin-dependent enhancement of growth hormone rhythmicity
Abstract
The physiological impact of ultradian temporal feeding patterns remains a major unanswered question in nutritional science. We have employed automated and nasogastric feeding to address this question in male rodents and human volunteers. While grazing and meal-feeding reduced food intake in parallel (compared to ad libitum-fed rodents), body length and tibial epiphysial plate width were maintained in meal-fed rodents via the action of ghrelin and its receptor, GHS-R. Grazing and meal-feeding initially suppressed elevated pre-prandial ghrelin levels in rats, followed by either a sustained elevation in ghrelin in grazing rats or pre-prandial ghrelin surges in meal-fed rats. Episodic growth hormone (GH) secretion was largely unaffected in grazing rats, but meal-feeding tripled GH secretion, with burst height augmented and two additional bursts of GH per day. Continuous nasogastric infusion of enteral feed in humans failed to suppress circulating ghrelin, producing continuously elevated circulating GH with minimal rhythmicity. In contrast, bolus enteral infusion elicited post-prandial ghrelin troughs accompanied by reduced circulating GH, with enhanced ultradian rhythmicity. Taken together, our data imply that the contemporary shift from regular meals to snacking behaviour may be detrimental to optimal skeletal growth outcomes by sustaining circulating GH at levels associated with undernourishment and diminishing GH pulsatility.
Authors
Amanda K.E. Hornsby, Richard C. Brown, Thomas W. Tilston, Harry A. Smith, Alfonso Moreno-Cabañas, Bradley Arms-Williams, Anna L. Hopkins, Katie D. Taylor, Simran K.R. Rogaly, Lois H.M. Wells, Jamie J. Walker, Jeffrey S. Davies, Yuxiang Sun, Jeffrey M. Zigman, James A. Betts, Timothy Wells
Abstract
Aberrant RNA splicing is tightly linked to diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we revealed that minor intron splicing, a unique and conserved RNA processing event, is largely disrupted upon the progression of metabolic dysfunction-associated steatohepatitis (MASH) in mice and humans. We demonstrated deficiency of minor intron splicing in the liver induces MASH transition upon obesity-induced insulin resistance and LXR activation. Mechanistically, inactivation of minor intron splicing leads to minor intron retention of Insig1 and Insig2, resulting in premature termination of translation, which drives proteolytic activation of SREBP1c. This mechanism is conserved in human patients with MASH. Notably, disrupted minor intron splicing activates glutamine reductive metabolism for de novo lipogenesis through the induction of Idh1, which causes the accumulation of ammonia in the liver, thereby initiating hepatic fibrosis upon LXR activation. Ammonia clearance or IDH1 inhibition blocks hepatic fibrogenesis and mitigates MASH progression. More importantly, the overexpression of Zrsr1 restored minor intron retention and ameliorated the development of MASH, indicating that dysfunctional minor intron splicing is an emerging pathogenic mechanism that drives MASH progression. Additionally, reductive carboxylation flux triggered by minor intron retention in hepatocytes serves as a crucial checkpoint and potential target for MASH therapy.
Authors
Yinkun Fu, Xin Peng, Hongyong Song, Xiaoyun Li, Yang Zhi, Jieting Tang, Yifan Liu, Ding Chen, Wenyan Li, Jing Zhang, Jing Ma, Ming He, Yimin Mao, Xu-Yun Zhao
Abstract
The interplay between intracellular and intravascular lipolysis is crucial for maintaining circulating lipid levels and systemic energy homeostasis. Adipose triglyceride lipase (ATGL) and lipoprotein lipase (LPL), the primary triglyceride (TG) lipases responsible for these two spatially separate processes, are highly expressed in adipose tissue. Yet, their coordinated regulation remains undetermined. Here, we demonstrate that genetic ablation of G0S2, a specific inhibitory protein of ATGL, completely abolishes diet-induced hypertriglyceridemia and significantly attenuates atherogenesis in mice. These effects are attributed to enhanced whole-body TG clearance, not altered hepatic TG secretion. Specifically, G0S2 deletion increases circulating LPL concentration and activity, predominantly through LPL production from white adipose tissue (WAT). Strikingly, transplantation of G0S2-deficient WAT normalizes plasma TG levels in mice with hypertriglyceridemia. In conjunction with improved insulin sensitivity and decreased ANGPTL4 expression, the absence of G0S2 enhances the stability of LPL protein in adipocytes, a phenomenon that can be reversed upon ATGL inhibition. Collectively, these findings highlight the pivotal role of adipocyte G0S2 in regulating both intracellular and intravascular lipolysis, and the possibility of targeting G0S2 as a viable pharmacological approach to reduce circulating TGs.
Authors
Yongbin Chen, Scott M. Johnson, Stephanie D. Burr, Davide Povero, Aaron M. Anderson, Cailin E. McMahon, Jun Liu
Abstract
BACKGROUND. Hyperinsulinemia and insulin resistance often accompany elevated serum urate levels (hyperuricemia), a highly heritable condition that triggers gout; however, the underlying mechanisms are unclear. METHODS. We evaluated the association between the index of hyperinsulinemia and the fractional excretion of urate (FEUA) in 162 outpatients. The underlying mechanisms were investigated through single-cell data analysis and kinase screening combined with cell culture experiments. In 377,358 participants of the UK Biobank (UKBB), we analyzed serum urate, hyperinsulinemia, and salt intake. We also examined gene-environment interactions using single nucleotide variants in SLC22A12, which encodes urate transporter 1 (URAT1). RESULTS. The index of hyperinsulinemia was inversely associated with FEUA independently of other covariates. Mechanistically, URAT1 cell-surface abundance and urate transport activity were regulated by URAT1-Thr408 phosphorylation, which was stimulated by hyperinsulinemia via AKT. Kinase screening and single-cell data analysis revealed that SGK1, induced by high salt, activated the same pathway, increasing URAT1. Arg405 was essential for these kinases to phosphorylate URAT1-Thr408. In UKBB participants, hyperinsulinemia and high salt intake were independently associated with increased serum urate levels. We found that SLC22A12 eQTL rs475688 synergistically enhanced the positive association between serum urate and hyperinsulinemia. CONCLUSION. URAT1 mediates the association between hyperinsulinemia and hyperuricemia. Our data provide evidence for the role of gene-environment interactions in determining serum urate levels, paving the way for personalized management of hyperuricemia. FUNDING. ACRO Research Grants of Teikyo University; JSPS; the Japanese Society of Gout and Uric & Nucleic Acids; Fuji Yakuhin; Nanken-Kyoten; Medical Research Center Initiative for High Depth Omics.
Authors
Wataru Fujii, Osamu Yamazaki, Daigoro Hirohama, Ken Kaseda, Emiko Kuribayashi-Okuma, Motonori Tsuji, Makoto Hosoyamada, Yuta Kochi, Shigeru Shibata
Abstract
BACKGROUND This study examined the underlying cellular mechanisms associated with insulin resistance (IR) and metabolic disease risk within subcutaneous adipose tissue (SAT) in youth with obesity and IR compared with those without IR.METHODS Thirteen adolescents who were insulin sensitive (IS) and 17 adolescents with IR and obesity underwent a 3-hour oral glucose tolerance test and MRI to measure abdominal fat distribution and liver fat content. Lipolysis was determined by glycerol turnover ([2H5]-glycerol infusion) and adipose triglyceride lipase (ATGL) phosphorylation (Western blot) from SAT samples biopsied prior to and 30-minutes following insulin infusion during a hyperinsulinemic-euglycemic clamp (HEC).RESULTS Glycerol turnover suppression during the HEC (first step) was lower in participants with IR compared with those with IS. Prior to insulin infusion, activated ATGL (reflected by the p-ATGL (Ser406)-to-ATGL ratio) was greater in participants with IR compared with those with IS and suppressed in response to a 30-minute insulin exposure in participants with IS, but not in those with IR. Lastly, greater ATGL inactivation is associated with greater glycerol suppression and lower liver fat.CONCLUSIONS Insulin-mediated inhibition of adipose tissue lipolysis via ATGL is dysregulated among adolescents with IR compared with those with IS, thereby serving as a vital mechanism linking glucose and insulin dysregulation and ectopic lipid storage within the liver.FUNDING This work was supported by funding from the NIH (R01-HD028016-25A1, T32- DK-007058, R01-DK124272, RO1-DK119968, R01MD015974, RO1-DK113984, P3-DK045735, RO1-DK133143, and RC2-DK120534) and the Robert E. Leet and Clara Guthrie Patterson Trust Mentored Research Award.
Authors
Aaron L. Slusher, Nicola Santoro, Alla Vash-Margita, Alfonso Galderisi, Pamela Hu, Fuyuze Tokoglu, Zhongyao Li, Elena Tarabra, Jordan Strober, Daniel F. Vatner, Gerald I. Shulman, Sonia Caprio
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ISSN: 0021-9738 (print), 1558-8238 (online)