bims-obesme 2024-05-26 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024–05–26
fiveteen papers selected by
Xiong Weng, University of Edinburgh

Hepatic Activin E mediates liver-adipose inter-organ communication, suppressing adipose lipolysis in response to elevated serum fatty acids.
Epigenetically active chromatin in neonatal iWAT reveals GABPα as a potential regulator of beige adipogenesis.
PPA1 promotes adipogenesis by regulating the stability of C/EBPs.
Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance.
Transcriptional control of metabolism by interferon regulatory factors.
Reduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice.
Insulin Hypersecretion as Promoter of Body Fat Gain and Hyperglycemia.
Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis.
Low MBOAT7 expression, a genetic risk for MASH, promotes a pro-fibrotic pathway involving hepatocyte TAZ upregulation.
Adipocyte HSL is required for maintaining circulating vitamin A and RBP4 levels during fasting.
T cells in obesity-associated inflammation: The devil is in the details.
Interaction between the gut microbiota and colonic enteroendocrine cells regulates host metabolism.
Circulating total and H-specific GDF15 levels are elevated in subjects with MASLD but not in hyperlipidemic but otherwise metabolically healthy subjects with obesity.
SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.
Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation.

Mol Metab. 2023 Dec;pii: S2212-8778(23)00164-3. [Epub ahead of print]78 101830

Hepatic Activin E mediates liver-adipose inter-organ communication, suppressing adipose lipolysis in response to elevated serum fatty acids.

John D Griffin, Joanne M Buxton, Jeffrey A Culver, Robert Barnes, Emily A Jordan, Alexis R White, Stephen E Flaherty, Barbara Bernardo, Trenton Ross, Kendra K Bence, Morris J Birnbaum.

   OBJECTIVE: The liver is a central regulator of energy metabolism exerting its influence both through intrinsic processing of substrates such as glucose and fatty acid as well as by secreting endocrine factors, known as hepatokines, which influence metabolism in peripheral tissues. Human genome wide association studies indicate that a predicted loss-of-function variant in the Inhibin βE gene (INHBE), encoding the putative hepatokine Activin E, is associated with reduced abdominal fat mass and cardiometabolic disease risk. However, the regulation of hepatic Activin E and the influence of Activin E on adiposity and metabolic disease are not well understood. Here, we examine the relationship between hepatic Activin E and adipose metabolism, testing the hypothesis that Activin E functions as part of a liver-adipose, inter-organ feedback loop to suppress adipose tissue lipolysis in response to elevated serum fatty acids and hepatic fatty acid exposure.
METHODS: The relationship between hepatic Activin E and non-esterified fatty acids (NEFA) released from adipose lipolysis was assessed in vivo using fasted CL 316,243 treated mice and in vitro using Huh7 hepatocytes treated with fatty acids. The influence of Activin E on adipose lipolysis was examined using a combination of Inhbe knockout mice, a mouse model of hepatocyte-specific overexpression of Activin E, and mouse brown adipocytes treated with Activin E enriched media.
RESULTS: Increasing hepatocyte NEFA exposure in vivo by inducing adipose lipolysis through fasting or CL 316,243 treatment increased hepatic Inhbe expression. Similarly, incubation of Huh7 human hepatocytes with fatty acids increased expression of INHBE. Genetic ablation of Inhbe in mice increased fasting circulating NEFA and hepatic triglyceride accumulation. Treatment of mouse brown adipocytes with Activin E conditioned media and overexpression of Activin E in mice suppressed adipose lipolysis and reduced serum FFA levels, respectively. The suppressive effects of Activin E on lipolysis were lost in CRISPR-mediated ALK7 deficient cells and ALK7 kinase deficient mice. Disruption of the Activin E-ALK7 signaling axis in Inhbe KO mice reduced adiposity upon HFD feeding, but caused hepatic steatosis and insulin resistance.
CONCLUSIONS: Taken together, our data suggest that Activin E functions as part of a liver-adipose feedback loop, such that in response to increased serum free fatty acids and elevated hepatic triglyceride, Activin E is released from hepatocytes and signals in adipose through ALK7 to suppress lipolysis, thereby reducing free fatty acid efflux to the liver and preventing excessive hepatic lipid accumulation. We find that disrupting this Activin E-ALK7 inter-organ communication network by ablation of Inhbe in mice increases lipolysis and reduces adiposity, but results in elevated hepatic triglyceride and impaired insulin sensitivity. These results highlight the liver-adipose, Activin E-ALK7 signaling axis as a critical regulator of metabolic homeostasis.

Keywords:  Adipose tissue; Diabetes; Lipolysis; Obesity

DOI:  https://doi.org/10.1016/j.molmet.2023.101830
Front Endocrinol (Lausanne). 2024 ;15 1385811

Epigenetically active chromatin in neonatal iWAT reveals GABPα as a potential regulator of beige adipogenesis.

Raja Gopal Reddy Mooli, Bokai Zhu, Saifur R Khan, Veerababu Nagati, Kulandaimanuvel Antony Michealraj, Michael J Jurczak, Sadeesh K Ramakrishnan.

   Background: Thermogenic beige adipocytes, which dissipate energy as heat, are found in neonates and adults. Recent studies show that neonatal beige adipocytes are highly plastic and contribute to >50% of beige adipocytes in adults. Neonatal beige adipocytes are distinct from recruited beige adipocytes in that they develop independently of temperature and sympathetic innervation through poorly defined mechanisms.
Methods: We characterized the neonatal beige adipocytes in the inguinal white adipose tissue (iWAT) of C57BL6 postnatal day 3 and 20 mice (P3 and P20) by imaging, genome-wide RNA-seq analysis, ChIP-seq analysis, qRT-PCR validation, and biochemical assays.
Results: We found an increase in acetylated histone 3 lysine 27 (H3K27ac) on the promoter and enhancer regions of beige-specific gene UCP1 in iWAT of P20 mice. Furthermore, H3K27ac ChIP-seq analysis in the iWAT of P3 and P20 mice revealed strong H3K27ac signals at beige adipocyte-associated genes in the iWAT of P20 mice. The integration of H3K27ac ChIP-seq and RNA-seq analysis in the iWAT of P20 mice reveal epigenetically active signatures of beige adipocytes, including oxidative phosphorylation and mitochondrial metabolism. We identify the enrichment of GA-binding protein alpha (GABPα) binding regions in the epigenetically active chromatin regions of the P20 iWAT, particularly on beige genes, and demonstrate that GABPα is required for beige adipocyte differentiation. Moreover, transcriptomic analysis and glucose oxidation assays revealed increased glycolytic activity in the neonatal iWAT from P20.
Conclusions: Our findings demonstrate that epigenetic mechanisms regulate the development of peri-weaning beige adipocytes via GABPα. Further studies to better understand the upstream mechanisms that regulate epigenetic activation of GABPα and characterization of the metabolic identity of neonatal beige adipocytes will help us harness their therapeutic potential in metabolic diseases.

Keywords:  GABPA; beige adipocyte; epigenetic modification; neonatal adipose tissue; subcutaneous adipose tissue

DOI:  https://doi.org/10.3389/fendo.2024.1385811
Cell Death Differ. 2024 May 18.

PPA1 promotes adipogenesis by regulating the stability of C/EBPs.

Yangyang Wu, Yue Sun, Yuqing Song, Jiateng Wang, Ye Han, Nan Yang, Haiyan Lin, Ye Yin, Xiao Han.

Adipogenesis significantly contributes to healthy adipose tissue expansion in obesity. Increasing adipocyte number or function to alleviate adipose tissue overload could serve as a therapeutic strategy for both lipodystrophy and obesity-related metabolic syndrome. Inorganic pyrophosphatase (PPA1) is an enzyme that catalyzes the hydrolysis of pyrophosphate (PPi) and is involved in many biochemical reactions, but its function in adipose tissue has not been studied previously. In this study, we demonstrated that adipose-specific PPA1 knockout (PPA1AKO) mice showed lipodystrophy and spontaneously developed hepatic steatosis and severe insulin resistance under normal chow diet feeding. PPA1 deficiency suppressed the differentiation of primary adipocyte precursors and 3T3-L1 cells. Notably, PPA1 overexpression can restore inhibited adipogenesis in preadipocytes isolated from db/db mice and type 2 diabetes patients. Mechanistic studies have revealed that PPA1 acts as a positive regulator of early adipocyte differentiation by promoting CCAAT/enhancer-binding proteinβ and δ (C/EBPβ and δ) protein stability. Moreover, the function of PPA1 in adipogenesis is independent of its PPi catalytic activity. Collectively, our in vivo and in vitro findings demonstrated that PPA1 is a novel critical upstream regulator of adipogenesis, controlling adipose tissue development and whole-body metabolic homeostasis.

DOI: https://doi.org/10.1038/s41418-024-01309-2
Immunity. 2024 May 14. pii: S1074-7613(24)00229-2. [Epub ahead of print]

Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance.

Jiping Sun, Youqin Zhang, Qingbing Zhang, Lin Hu, Linfeng Zhao, Hongdong Wang, Yue Yuan, Hongshen Niu, Dongdi Wang, Huasheng Zhang, Jianyue Liu, Xujiao Feng, Xiaohui Su, Ju Qiu, Jing Sun, Heping Xu, Catherine Zhang, Kathleen Wang, Yan Bi, Edgar G Engleman, Lei Shen.

  Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.

Keywords:  PD-1; group 2 innate lymphoid cells; insulin resistance; liver kinase B1; mitophagy

DOI:  https://doi.org/10.1016/j.immuni.2024.04.024
Nat Rev Endocrinol. 2024 May 20.

Transcriptional control of metabolism by interferon regulatory factors.

Zunair Ahmad, Wahab Kahloan, Evan D Rosen.

Interferon regulatory factors (IRFs) comprise a family of nine transcription factors in mammals. IRFs exert broad effects on almost all aspects of immunity but are best known for their role in the antiviral response. Over the past two decades, IRFs have been implicated in metabolic physiology and pathophysiology, partly as a result of their known functions in immune cells, but also because of direct actions in adipocytes, hepatocytes, myocytes and neurons. This Review focuses predominantly on IRF3 and IRF4, which have been the subject of the most intense investigation in this area. IRF3 is located in the cytosol and undergoes activation and nuclear translocation in response to various signals, including stimulation of Toll-like receptors, RIG-I-like receptors and the cGAS-STING pathways. IRF3 promotes weight gain, primarily by inhibiting adipose thermogenesis, and also induces inflammation and insulin resistance using both weight-dependent and weight-independent mechanisms. IRF4, meanwhile, is generally pro-thermogenic and anti-inflammatory and has profound effects on lipogenesis and lipolysis. Finally, new data are emerging on the role of other IRF family members in metabolic homeostasis. Taken together, data indicate that IRFs serve as critical yet underappreciated integrators of metabolic and inflammatory stress.

DOI: https://doi.org/10.1038/s41574-024-00990-0
Nat Commun. 2024 May 23. 15(1): 4393

Reduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice.

Yuan Liang, Chao Luo, Lijun Sun, Tiange Feng, Wenzhen Yin, Yunhua Zhang, Michael W Mulholland, Weizhen Zhang, Yue Yin.

Whether intestinal Leucine-rich repeat containing G-protein-coupled receptor 4 (LGR4) impacts nutrition absorption and energy homeostasis remains unknown. Here, we report that deficiency of Lgr4 (Lgr4iKO) in intestinal epithelium decreased the proportion of enterocytes selective for long-chain fatty acid absorption, leading to reduction in lipid absorption and subsequent improvement in lipid and glucose metabolism. Single-cell RNA sequencing demonstrates the heterogeneity of absorptive enterocytes, with a decrease in enterocytes selective for long-chain fatty acid-absorption and an increase in enterocytes selective for carbohydrate absorption in Lgr4iKO mice. Activation of Notch signaling and concurrent inhibition of Wnt signaling are observed in the transgenes. Associated with these alterations is the substantial reduction in lipid absorption. Decrement in lipid absorption renders Lgr4iKO mice resistant to high fat diet-induced obesity relevant to wild type littermates. Our study thus suggests that targeting intestinal LGR4 is a potential strategy for the intervention of obesity and liver steatosis.

DOI: https://doi.org/10.1038/s41467-024-48622-5
Diabetes. 2024 Jun 01. 73(6): 837-843

Insulin Hypersecretion as Promoter of Body Fat Gain and Hyperglycemia.

Bettina Mittendorfer, James D Johnson, Giovanni Solinas, Per-Anders Jansson.

DOI: https://doi.org/10.2337/dbi23-0035
Nat Commun. 2024 May 18. 15(1): 4232

Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis.

Pai Wang, Xin Yang, Luyao Zhang, Sha Sha, Juan Huang, Jian Peng, Jianlei Gu, James Alexander Pearson, Youjia Hu, Hongyu Zhao, F Susan Wong, Quan Wang, Li Wen.

Toll-like receptor 9 (TLR9) recognizes bacterial, viral and self DNA and play an important role in immunity and inflammation. However, the role of TLR9 in obesity is less well-studied. Here, we generate B-cell-specific Tlr9-deficient (Tlr9fl/fl/Cd19Cre+/-, KO) B6 mice and model obesity using a high-fat diet. Compared with control mice, B-cell-specific-Tlr9-deficient mice exhibited increased fat tissue inflammation, weight gain, and impaired glucose and insulin tolerance. Furthermore, the frequencies of IL-10-producing-B cells and marginal zone B cells were reduced, and those of follicular and germinal center B cells were increased. This was associated with increased frequencies of IFNγ-producing-T cells and increased follicular helper cells. In addition, gut microbiota from the KO mice induced a pro-inflammatory state leading to immunological and metabolic dysregulation when transferred to germ-free mice. Using 16 S rRNA gene sequencing, we identify altered gut microbial communities including reduced Lachnospiraceae, which may play a role in altered metabolism in KO mice. We identify an important network involving Tlr9, Irf4 and Il-10 interconnecting metabolic homeostasis, with the function of B and T cells, and gut microbiota in obesity.

DOI: https://doi.org/10.1038/s41467-024-48611-8
Hepatology. 2024 May 22.

Low MBOAT7 expression, a genetic risk for MASH, promotes a pro-fibrotic pathway involving hepatocyte TAZ upregulation.

Mary P Moore, Xiaobo Wang, John Paul Kennelly, Hongxue Shi, Yuki Ishino, Kuniyuki Kano, Junken Aoki, Alessandro Cherubini, Luisa Ronzoni, Xiuqing Guo, Naga P Chalasani, Shareef Khalid, Danish Saleheen, Mathew A Mitsche, Jerome I Rotter, Katherine P Yates, Luca Valenti, Nozomu Kono, Peter Tontonoz, Ira Tabas.

BACKGROUND AND AIMS: The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established MASLD dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear.
APPROACH AND RESULTS: We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity, and increased IHH mRNA.
CONCLUSIONS: This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis; adds new insight into an established genetic locus for MASH; and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7.

DOI: https://doi.org/10.1097/HEP.0000000000000933
EMBO Rep. 2024 May 20.

Adipocyte HSL is required for maintaining circulating vitamin A and RBP4 levels during fasting.

Julia S Steinhoff, Carina Wagner, Henriette E Dähnhardt, Kristina Košić, Yueming Meng, Ulrike Taschler, Laura Pajed, Na Yang, Sascha Wulff, Marie F Kiefer, Konstantin M Petricek, Roberto E Flores, Chen Li, Sarah Dittrich, Manuela Sommerfeld, Hervé Guillou, Andrea Henze, Jens Raila, Sylvia J Wowro, Gabriele Schoiswohl, Achim Lass, Michael Schupp.

  Vitamin A (retinol) is distributed via the blood bound to its specific carrier protein, retinol-binding protein 4 (RBP4). Retinol-loaded RBP4 is secreted into the circulation exclusively from hepatocytes, thereby mobilizing hepatic retinoid stores that represent the major vitamin A reserves in the body. The relevance of extrahepatic retinoid stores for circulating retinol and RBP4 levels that are usually kept within narrow physiological limits is unknown. Here, we show that fasting affects retinoid mobilization in a tissue-specific manner, and that hormone-sensitive lipase (HSL) in adipose tissue is required to maintain serum concentrations of retinol and RBP4 during fasting in mice. We found that extracellular retinol-free apo-RBP4 induces retinol release by adipocytes in an HSL-dependent manner. Consistently, global or adipocyte-specific HSL deficiency leads to an accumulation of retinoids in adipose tissue and a drop of serum retinol and RBP4 during fasting, which affects retinoid-responsive gene expression in eye and kidney and lowers renal retinoid content. These findings establish a novel crosstalk between liver and adipose tissue retinoid stores for the maintenance of systemic vitamin A homeostasis during fasting.

Keywords:  Fasting; HSL; RBP4; Retinol; Vitamin A

DOI:  https://doi.org/10.1038/s44319-024-00158-x
Immunol Rev. 2024 May 20.

T cells in obesity-associated inflammation: The devil is in the details.

Yolander Valentine, Barbara S Nikolajczyk.

  Obesity presents a significant health challenge, affecting 41% of adults and 19.7% of children in the United States. One of the associated health challenges of obesity is chronic low-grade inflammation. In both mice and humans, T cells in circulation and in the adipose tissue play a pivotal role in obesity-associated inflammation. Changes in the numbers and frequency of specific CD4+ Th subsets and their contribution to inflammation through cytokine production indicate declining metabolic health, that is, insulin resistance and T2D. While some Th subset alterations are consistent between mice and humans with obesity, some changes mainly characterize male mice, whereas female mice often resist obesity and inflammation. However, protection from obesity and inflammation is not observed in human females, who can develop obesity-related T-cell inflammation akin to males. The decline in female sex hormones after menopause is also implicated in promoting obesity and inflammation. Age is a second underappreciated factor for defining and regulating obesity-associated inflammation toward translating basic science findings to the clinic. Weight loss in mice and humans, in parallel with these other factors, does not resolve obesity-associated inflammation. Instead, inflammation persists amid modest changes in CD4+ T cell frequencies, highlighting the need for further research into resolving changes in T-cell function after weight loss. How lingering inflammation after weight loss affecting the common struggle to maintain lower weight is unknown. Semaglutide, a newly popular pharmaceutical used for treating T2D and reversing obesity, holds promise for alleviating obesity-associated health complications, yet its impact on T-cell-mediated inflammation remains unexplored. Further work in this area could significantly contribute to the scientific understanding of the impacts of weight loss and sex/hormones in obesity and obesity-associated metabolic decline.

Keywords:  Type 2 diabetes; aging; inflammation; regulatory T cells; sex differences

DOI:  https://doi.org/10.1111/imr.13354
Nat Metab. 2024 May 22.

Interaction between the gut microbiota and colonic enteroendocrine cells regulates host metabolism.

Shuai Tan, Jacobo L Santolaya, Tiffany Freeney Wright, Qi Liu, Teppei Fujikawa, Sensen Chi, Colin P Bergstrom, Adam Lopez, Qing Chen, Goncalo Vale, Jeffrey G McDonald, Andrew Schmidt, Nguyen Vo, Jiwoong Kim, Hamid Baniasadi, Li Li, Gaohui Zhu, Tong-Chuan He, Xiaowei Zhan, Yuuki Obata, Aishun Jin, Da Jia, Joel K Elmquist, Luis Sifuentes-Dominguez, Ezra Burstein.

Nutrient handling is an essential function of the gastrointestinal tract. Hormonal responses of small intestinal enteroendocrine cells (EECs) have been extensively studied but much less is known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs. Here we show that colonic EEC deficiency leads to hyperphagia and obesity. Furthermore, colonic EEC deficiency results in altered microbiota composition and metabolism, which we found through antibiotic treatment, germ-free rederivation and transfer to germ-free recipients, to be both necessary and sufficient for the development of obesity. Moreover, studying stool and blood metabolomes, we show that differential glutamate production by intestinal microbiota corresponds to increased appetite and that colonic glutamate administration can directly increase food intake. These observations shed light on an unanticipated host-microbiota axis in the colon, part of a larger gut-brain axis, that regulates host metabolism and body weight.

DOI: https://doi.org/10.1038/s42255-024-01044-5
Cardiovasc Diabetol. 2024 May 18. 23(1): 174

Circulating total and H-specific GDF15 levels are elevated in subjects with MASLD but not in hyperlipidemic but otherwise metabolically healthy subjects with obesity.

Chrysoula Boutari, Konstantinos Stefanakis, Stamatia Simati, Valentina Guatibonza-García, Laura Valenzuela-Vallejo, Ioanna A Anastasiou, Margery A Connelly, Alexander Kokkinos, Christos S Mantzoros.

   BACKGROUND: Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD.
METHODS: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed.
RESULTS: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders.
CONCLUSION: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946.

Keywords:  C-peptide; GIP; Growth differentiation factor 15; Mixed meal test; Non-alcoholic fatty liver disease; Obesity; Oral glucose tolerance test

DOI:  https://doi.org/10.1186/s12933-024-02264-5
Cell Stem Cell. 2024 May 14. pii: S1934-5909(24)00176-0. [Epub ahead of print]

SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.

Shintaro Watanuki, Hiroshi Kobayashi, Yuki Sugiura, Masamichi Yamamoto, Daiki Karigane, Kohei Shiroshita, Yuriko Sorimachi, Takayuki Morikawa, Shinya Fujita, Kotaro Shide, Miho Haraguchi, Shinpei Tamaki, Takumi Mikawa, Hiroshi Kondoh, Hiroyasu Nakano, Kenta Sumiyama, Go Nagamatsu, Nobuhito Goda, Shinichiro Okamoto, Ayako Nakamura-Ishizu, Kazuya Shimoda, Makoto Suematsu, Toshio Suda, Keiyo Takubo.

  Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis. Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resilience that promotes cell survival. High-resolution real-time ATP analysis with glucose tracing and metabolic flux analysis revealed that old HSCs reprogram their metabolism to activate the pentose phosphate pathway (PPP), becoming more resistant to oxidative stress and less dependent on glycolytic ATP production at steady state. As a result, old HSCs can survive without glycolysis, adapting to the physiological cytokine environment in bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolism during stress to promote ATP production. Furthermore, increased succinate dehydrogenase assembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentration thrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolic stress, thereby improving survival. This study provides insight into the acquisition of resilience through metabolic reprogramming in old HSCs and its molecular basis to ameliorate age-related hematopoietic abnormalities.

Keywords:  SDHAF1; adenosine triphosphate; hematopoietic stem cell; mitochondria; stem cell aging; stem cell metabolism; thrombopoietin

DOI:  https://doi.org/10.1016/j.stem.2024.04.023
Nat Commun. 2024 May 18. 15(1): 4235

Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation.

Gan Zhao, Maria E Gentile, Lulu Xue, Christopher V Cosgriff, Aaron I Weiner, Stephanie Adams-Tzivelekidis, Joanna Wong, Xinyuan Li, Sara Kass-Gergi, Nicolas P Holcomb, Maria C Basal, Kathleen M Stewart, Joseph D Planer, Edward Cantu, Jason D Christie, Maria M Crespo, Michael J Mitchell, Nuala J Meyer, Andrew E Vaughan.

Inflammation induced by lung infection is a double-edged sword, moderating both anti-viral and immune pathogenesis effects; the mechanism of the latter is not fully understood. Previous studies suggest the vasculature is involved in tissue injury. Here, we report that expression of Sparcl1, a secreted matricellular protein, is upregulated in pulmonary capillary endothelial cells (EC) during influenza-induced lung injury. Endothelial overexpression of SPARCL1 promotes detrimental lung inflammation, with SPARCL1 inducing 'M1-like' macrophages and related pro-inflammatory cytokines, while SPARCL1 deletion alleviates these effects. Mechanistically, SPARCL1 functions through TLR4 on macrophages in vitro, while TLR4 inhibition in vivo ameliorates excessive inflammation caused by endothelial Sparcl1 overexpression. Finally, SPARCL1 expression is increased in lung ECs from COVID-19 patients when compared with healthy donors, while fatal COVID-19 correlates with higher circulating SPARCL1 protein levels in the plasma. Our results thus implicate SPARCL1 as a potential prognosis biomarker for deadly COVID-19 pneumonia and as a therapeutic target for taming hyperinflammation in pneumonia.

DOI: https://doi.org/10.1038/s41467-024-48589-3