Metabolism
Abstract
Obesity is accompanied by increases in free fatty acids (FFAs) in the systemic circulation, and obese patients often develop cardiac hypertrophy and diastolic dysfunction, termed obesity cardiomyopathy. Proinflammatory cytokines, including IL-6, have been implicated in the pathogenesis of the cardiac dysfunction associated with obesity cardiomyopathy. Elevation of FFAs induced by high fat diet (HFD) consumption induced diastolic dysfunction in the heart as early as after one month. HFD consumption directly stimulated IL-6 production in cardiomyocytes before local inflammation developed and induced diastolic dysfunction even in the presence of macrophage depletion with clodronate in the heart. PPARα played an essential role in mediating Il6 transcription in response to HFD consumption by forming a heterodimer with p50/RelA and binding to the NFκB element in cardiomyocytes. Local production of IL-6 in cardiomyocytes, in turn, mediated the development of diastolic cardiac dysfunction. HFD-induced diastolic dysfunction was attenuated by cardiac-specific deletion of either Ppara or Il6, as well as by interference with the PPARα-NFκB heterodimer formation by a molecular decoy. These results suggest that elevated FFAs directly upregulate Il6 through the PPARα-NFκB heterodimer in cardiomyocytes and highlight autocrine production of IL-6 as a key downstream mechanism in the initial development of diastolic dysfunction.
Authors
Shin-ichi Oka, Eun-Ah Sung, Peiyong Zhai, Kevin B. Schesing, Santosh Bhat, Adave Chin, Jiyeon Park, Yeun-Jun Chung, Akihiro Shirakabe, Takanobu Yamamoto, Yoshiyuki Ikeda, Wataru Mizushima, Shohei Ikeda, Mingming Tong, Jaemin Byun, Michinari Nakamura, Samuel I. Kim, Jamie Francisco, Dominic P. Del Re, Junichi Sadoshima
Abstract
Background Youth with type 2 diabetes (T2D) and severe obesity face high risk of diabetic kidney disease, which metabolic bariatric surgery (MBS) can mitigate. This study explores structural and molecular changes in kidneys after vertical sleeve gastrectomy (VSG), a form of MBS. Methods Paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNAseq) on kidney biopsies from five youth with T2D and obesity pre- and 12 months post-VSG in the IMPROVE-T2D (Impact of Metabolic surgery on Pancreatic, Renal and cardiOVascular hEalth in youth with T2D) cohort. Circulating proteomics with kidney transcriptomics, were linked using data from an independent cohort of youth with obesity, with or without T2D, undergoing MBS in Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n=64). Results Post-VSG, participants lost weight and had improvements in insulin sensitivity and metabolic parameters. Kidney changes included reduced renal hyperfiltration, total kidney volume, mesangial matrix area, and microalbuminuria. scRNAseq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid cycle genes, with upregulation of AMP-activated protein kinase (AMPK) and Forkhead box O3 (FOXO3). Decreased metabolic signaling aligned with reduced ribosomal phosphorylated S6K (pS6K), suggesting attenuated mTORC1 activity. JAK-STAT pathway activation in PT was diminished, correlating with lower circulating ligands from Teen-LABS proteomic data. Conclusion MBS/VSG prompts kidney molecular adaptations, providing potential targets for non-surgical interventions against obesity- and diabetes-associated kidney disease.
Authors
Abhijit S. Naik, Fadhl M. Alakwaa, Viji Nair, Phillip J. McCown, Jennifer A. Schaub, Edgar A. Otto, Rajasree Menon, Francesca Annese, Ye Ji Choi, Hailey E. Hampson, Thomas H. Inge, John Hartman, Sean Eddy, Cathy Smith, Jeffrey B. Hodgin, Ken Inoki, Swayam Prakash Srivastava, Kareem Al-Fagih, Shota Yoshida, Jesse A. Goodrich, Melanie G. Cree, Phoom Narongkiatikhun, Long Yuan, Kalie L. Tommerdahl, Pottumarthi Prasad, Daniël H. van Raalte, Megan M. Kelsey, Justin R. Ryder, Tyler J. Dobbs, Patricia Ladd, Subramaniam Pennathur, Robert G. Nelson, Yusuke Okabayashi, Victor G. Puelles, Jenna Ferrence-Salo, Jeffrey A. Beamish, Frank C. Brosius, Kristen J. Nadeau, Laura Pyle, Matthias Kretzler, Petter Bjornstad
Abstract
Ceramides are essential skin lipids for maintaining the mammalian skin permeability barrier, which protects against external stimuli. The precursor of epidermal ceramides, glucosylceramides (GlcCer), is synthesized within granular keratinocytes while its precise cellular transport mechanisms remain poorly characterized. Here, we identified three pathogenic variants in the GLTP gene, which encodes glycolipid transfer protein, in five unrelated families with nonsyndromic epidermal differentiation disorder presenting with generalized skin scaling. The biallelic GLTP variants resulted in loss of competent GLTP expression. CRISPR/Cas9-generated Gltp knockout mice exhibited lethal barrier defects, partially recapitulating the clinical features of our patients. We demonstrated that GLTP facilitated GlcCer transport in differentiated keratinocytes, with its deficiency causing impaired GlcCer trafficking and consequent aberrant retention in lysosomes, thereby disrupted lysosome function. The lysosomal dysfunction impaired autophagy flux, resulting in delayed keratinocyte terminal differentiation, which is expected to compromise the skin barrier integrity and ultimate abnormal scaling. Pharmaceutical inhibition of GlcCer synthesis effectively rescued both autophagy and keratinocyte differentiation defects. Our findings establish GLTP as a novel underlying gene for nonsyndromic epidermal differentiation disorders and unravel its essential role in maintaining skin homeostasis during terminal differentiation by mediating epidermal GlcCer transport.
Authors
Zeqiao Zhang, Shimiao Huang, Adam Jackson, Elizabeth A. Jones, Siddharth Banka, Chao Yang, Sisi Zhao, Kunlun Lv, Sha Peng, Zhimiao Lin, Huijun Wang
Abstract
Aging commonly causes decline of testosterone or estrogen, leading to overaccumulation of fatness in males or females, respectively. Although such phenomenon can be readily explained by estrogen’s direct action on adipocytes in females, accumulative evidence does not support the direct action of testosterone in adipocyte lipid metabolism, suggesting that there is a missing intermediary link. Herein, we propose that glycoprotein hormone β5 (GPHB5) is the intermediary linkage between testosterone and the regulation of adiposity. In clinical samples, blood levels of GPHB5 were correlated negatively with men’s ages, and positively with circulating testosterone. Testosterone directly stimulated the expression of GPHB5 in cultured cells, pharmacological blockade of androgen receptor (AR) functions abrogated such effect. Knockout of AR led to not only development of obesity but also reduction of GPHB5 expression. Genetic ablation of GPHB5 in the males, but not in the females, lowered the browning of white adipose tissue, diminished energy expenditure and caused severe obesity. Importantly, elevated blood testosterone didn’t exert its catabolic actions in GPHB5 null mice, and yet, recombinant GPHB5 protein was able to stimulate energy expenditure and reduce adiposity. Taken together, these results provided the strong proof that GPHB5 is the “missing” intermediary hormone linking testosterone (and aging) and its well-known catabolic effect on adipose tissue.
Authors
Gengmiao Xiao, Aijun Qian, Zhuo Gao, Tingting Dai, Hui Liang, Shuai Wang, Mulan Deng, Yunjing Yan, Xindan Zhang, Xuedi Zhang, Yunping Mu, Jiqiu Wang, Aibo Gao, Huijie Zhang, Fanghong Li, Allan Zijian Zhao
Abstract
Lipodystrophy syndromes are marked by loss of adipose tissue (AT), which leads to insulin resistance and metabolic syndrome development. We identified a heterozygous nonsense variant in early B cell factor 2 (EBF2) (Chr8:26033143C>A, NM_022659.4: c.493G>T, p.E165X) in a patient with atypical partial lipodystrophy (PLD). The EBF family is crucial for the differentiation and function of various mesenchymal tissues. Through in vitro and in vivo disease models, we discovered that this variant limits adipocyte differentiation and hampers adipose tissue remodeling. Heterozygous knock-in (Ebf2E165X/+) mice showed restricted adipogenesis and defective extracellular matrix (ECM) remodeling during post-weaning and high-fat diet (HFD)-induced adipose tissue expansion. HFD caused abnormal adipocyte hypertrophy, decreased expression of adiponectin and leptin, and glucose intolerance in Ebf2E165X/+ mice. Furthermore, key mitochondrial genes involved in fatty acid metabolism and oxidation were specifically downregulated in the Ebf2E165X/+ adipose tissue. Our results suggest that EBF2 dysfunction driven by this nonsense variant drives disease pathology, establishing a connection between EBF2 disruption and an atypical form of lipodystrophy.
Authors
Maria C. Foss-Freitas, Donatella Gilio, Lynn Pais, Eric D. Buras, Romil Kaul Verma, Melanie O'Leary, Heidi L. Rehm, Carmen Glaze, Kathryn Russell, Andre Monteiro da Rocha, Adam Neidert, Patrick Seale, Miriam S. Udler, Elif A. Oral, Tae-Hwa Chun
Abstract
Authors
Johnathan R. Kent, Keene L. Abbott, Rachel Nordgren, Amy Deik, Nupur K. Das, Millenia Waite, Tenzin Kunchok, Anna Shevzov-Zebrun, Nathaniel Christiansen, Amir Sadek, Darren S. Bryan, Mark K. Ferguson, Jessica S. Donington, Alexander Muir, Yatrik M. Shah, Clary B. Clish, Matthew G. Vander Heiden, Maria Lucia L. Madariaga, Peggy P. Hsu
Abstract
The c-Jun N-terminal kinases (JNKs) regulate diverse physiological processes. Whereas JNK1 and JNK2 are broadly expressed and associated with insulin resistance, inflammation, and stress responses, JNK3 is largely restricted to central nervous system neurons and pancreatic β cells, and its physiological role in β cells remains poorly defined. To investigate its function, we generated mice lacking JNK3 specifically in β cells (βJNK3-KO). These mice displayed glucose intolerance and defective insulin secretion, particularly after oral glucose challenge, indicating impaired incretin responses. Consistently, Exendin-4–stimulated (Ex4-stimulated) insulin secretion was blunted in βJNK3-KO islets, accompanied by reduced GLP-1R expression. Similar findings were observed in human islets treated with a selective JNK3 inhibitor (iJNK3). Downstream of GLP-1R, Ex4-induced CREB phosphorylation was diminished in βJNK3-KO islets, indicating impaired canonical signaling. Moreover, activation of the GLP-1R/CREB/IRS2 pathway, a key regulator of β cell survival, was reduced in βJNK3-KO islets and iJNK3-treated human islets. As a consequence, the protective effects of Ex4 were lost in cytokine-treated βJNK3-KO and human islets, and Ex4-mediated protection was partially attenuated in βJNK3-KO mice exposed to multiple low-dose streptozotocin. These findings identify JNK3 as a regulator of β cell function and survival and suggest that targeting this pathway may enhance incretin-based therapies.
Authors
Ruy A. Louzada, Marel Gonzalez Medina, Valentina Pita-Grisanti, Jessica Bouviere, Amanda F. Neves, Joana Almaça, Myoung Sook Han, Roger J. Davis, Gil Leibowitz, Manuel Blandino-Rosano, Ernesto Bernal-Mizrachi
Abstract
Calorie restriction (CR) extends maximal lifespan and maintains cellular homeostasis in various animal models. We have previously shown that CR induces a global reduction of protein fractional synthesis rates (FSRs) across the hepatic proteome in mice, but the timing and regulatory mechanisms remain unclear. Nitric oxide (NO), a bioactive molecule upregulated during CR, is a potential regulator of protein synthesis. To explore the role of NO in hepatic proteome fluxes during CR, we used in vivo deuterium labeling from heavy water and liquid chromatography/mass spectrometry–based (LC/MS-based) flux proteomics in WT and NO-deficient (NO–) mice. We observed a transition to reduced global protein FSRs that occurred rapidly between days 25 and 30 of CR. NO deficiency, whether genetic or pharmacological, disrupted the slowing of proteome-wide fluxes and the beneficial effects on body composition and physiology. Administering the NO donor molsidomine restored the reduction in hepatic FSRs in NO– mice. Furthermore, inhibiting NO pharmacologically, whether starting on day 1, day 14, or day 24 of CR, mitigated the reduction in hepatic protein FSRs at day 32, highlighting NO’s critical role during the transition period. These results underscore the importance of NO in CR-induced changes in proteostasis and suggest NO as a potential CR-mimetic target, while offering a specific time window for identifying other signals and testing therapeutic interventions.
Authors
Hector H. Palacios, Edward Cao, Adelaide Cahill, Hussein Mohamad, Marc K. Hellerstein
Abstract
BACKGROUND. Amino acid (AA) concentrations are increased in prediabetes and diabetes. Since AA stimulate glucagon secretion which should then increase hepatic AA catabolism, it has been hypothesized that hepatic resistance (associated with hepatic fat content) to glucagon’s actions on AA metabolism leads to hyperglucagonemia and hyperglycemia. METHODS. To test this hypothesis, we therefore studied lean and obese individuals, the latter group with and without hepatic steatosis as defined by Proton Density Fat Fraction (PDFF) > 5%. After an overnight fast, femoral vein, femoral artery, and hepatic vein catheters were placed. [3-3H] glucose and L-[1-13C,15N]-leucine were used to measure glucose turnover and leucine oxidation respectively. During a hyperglycemic clamp, an amino acid mixture was infused together with insulin and glucagon (1.5 ng/kg/min 0 – 120 min; 3.0 ng/kg/min 120 – 240 min). Tracer-based measurement of hepatic leucine oxidation in response to rising glucagon concentrations and splanchnic balance (measured using arterio-venous differences across the liver), of the other AA were the main outcomes measured. RESULTS. The presence of hepatic steatosis did not alter hepatic glucose metabolism and leucine oxidation in response to insulin and rising concentrations of glucagon. Splanchnic balance of a few amino acids, and related metabolites differed amongst the groups. However, across-group differences of AA splanchnic balance in response to glucagon were unaffected by the presence of hepatic steatosis. CONCLUSION. The action of glucagon on hepatic amino acid metabolism is unaffected by hepatic steatosis in humans. TRIAL REGISTRATION. This study was registered at Clinical Trials.Gov: NCT05500586. FUNDING. This work was funding by the NIH.
Authors
Hannah E. Christie, Sneha Mohan, Aoife M. Egan, Federica Boscolo, Chiara Dalla Man, Scott M. Thompson, Michael Jundt, Chad J. Fleming, James C. Andrews, Kent R. Bailey, Michael D. Jensen, K. Sree Nair, Adrian Vella
Abstract
The metabolic microenvironment plays important roles in tumorigenesis, but how leukemia-initiating cells (LICs) response to the acidic BM niche remains largely unknown. Here, we show that acid-sensing ion channel 3 (ASIC3) dramatically delays leukemogenesis. Asic3 deletion results in a remarkably enhanced self-renewal, reduced differentiation, and 9-fold greater number of murine acute myeloid LICs. We developed an ultrasensitive, ratiometric, genetically encoded fluorescent pH sensor (pHluorin3) and demonstrated that LICs prefer localizing in the endosteal niche with a neutral pH range of 7.34–7.42, but not in the vascular niche with a lower pH range of 6.89–7.22. Unexpectedly, acid-ASIC3 signaling inhibits both murine and human LIC activities in a noncanonical manner by interacting with the N-terminal of STIM1 to reduce calcium-mediated CAMK1-CREB-MEIS1-LDHA levels, without inducing cation currents. This study reveals a pathway in suppression of leukemogenesis in the acidic BM niche and provides insight into targeting LICs or other cancer stem cells through pH-dependent ASICs.
Authors
Hao Gu, Lietao Weng, Chiqi Chen, Xiaoxin Hao, Rongkun Tao, Xin Qi, Xiaoyun Lai, Ligen Liu, Tinghua Zhang, Yiming Jiang, Jin Wang, Wei-Guang Li, Zhuo Yu, Li Xie, Yaping Zhang, Xiaoxiao He, Ye Yu, Yi Yang, Dehua Wu, Yuzheng Zhao, Tian-Le Xu, Guo-Qiang Chen, Junke Zheng
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)