bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–06–23
nine papers selected by
Xiong Weng, University of Edinburgh
  1. Polyamine metabolism in macrophage-adipose tissue function and homeostasis.
  2. Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communications.
  3. Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans.
  4. The PP2A regulatory subunit PPP2R2A controls NAD+ biosynthesis to regulate T cell subset differentiation in systemic autoimmunity.
  5. The lipopolysaccharide-TLR4 axis regulates hepatic glutaminase 1 expression promoting liver ammonia build-up as steatotic liver disease progresses to steatohepatitis.
  6. Exploring the role of macrophages in the pathogenesis of Alcohol-associated liver disease.
  7. SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit.
  8. Hepatic noradrenergic innervation acts via CREB/CRTC2 to activate gluconeogenesis during cold.
  9. The sphingosine-1-phosphate receptor 1 mediates the atheroprotective effect of eicosapentaenoic acid.
  1. Trends Endocrinol Metab. 2024 Jun 18. pii: S1043-2760(24)00126-7. [Epub ahead of print]
    Polyamine metabolism in macrophage-adipose tissue function and homeostasis.
    Didier F Pisani, Daniele Lettieri-Barbato, Stoyan Ivanov.
      Intracellular metabolism is a crucial regulator of macrophage function. Recent evidence revealed that the polyamine pathway and subsequent hypusination of eukaryotic initiation factor 5A (eIF5A) are master regulators of immune cell functions. In brown adipose tissue (BAT), macrophages show an impressive degree of heterogenicity, with specific subsets supporting adaptive thermogenesis during cold exposure. In this review, we discuss the impact of polyamine metabolism on macrophage diversity and function, with a particular focus on their role in adipose tissue homeostasis. Thus, we highlight the exploration of how polyamine metabolism in macrophages contributes to BAT homeostasis as an attractive and exciting new field of research.
    Keywords:  eIF5A; hypusination; inflammation; monocyte; thermogenesis
    DOI:  https://doi.org/10.1016/j.tem.2024.05.008
  2. J Clin Invest. 2024 Jun 18. pii: e178303. [Epub ahead of print]
    Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communications.
    Hui Wang, Shanshan Guo, Huanqing Gao, Jiyang Ding, Hongyun Li, Xingyu Kong, Shuang Zhang, Muyang He, Yonghao Feng, Wei Wu, Kexin Xu, Yuxuan Chen, Hanyin Zhang, Tiemin Liu, Xingxing Kong.
      Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been an increasing interest in its role in metabolism. In our study, we specifically knocked out MSTN in brown adipose tissue (BAT) from mice (MSTNΔUCP1) and found that the mice gained more weight than controls when fed a high-fat diet, with progressive hepatosteatosis and impaired skeletal muscle activity. RNA-seq analysis indicated signatures of mitochondrial dysfunction and inflammation in the MSTN-ablation BAT. Further studies demonstrated that the the Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, while FGF21 contributed to the microenvironment communication between adipocytes and macrophages induced by the loss of MSTN. Moreover, the MSTN-SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. In summary, our findings suggest that brown adipocytes-derived MSTN regulates BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis.
    Keywords:  Adipose tissue; Endocrinology
    DOI:  https://doi.org/10.1172/JCI178303
  3. Nat Commun. 2024 Jun 18. 15(1): 5190
    Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans.
    Pavlina Chrysafi, Laura Valenzuela-Vallejo, Konstantinos Stefanakis, Theodoros Kelesidis, Margery A Connelly, Christos S Mantzoros.
      Mitochondrial-secreted growth differentiation factor-15 (GDF-15) promotes weight loss in animals. Its effects in humans remain unclear, due to limited research and potential measurement interference from the H202D-variant. Our post-hoc analysis investigates total (irrespective of genetic variants) and H-specific GDF-15 (detected only in H202D-variant absence) in humans under acute and chronic energy deprivation, examining GDF-15 interaction with leptin (energy homeostasis regulator) and GDF-15 biologic activity modulation by the H202D-variant. Total and H-specific GDF-15 increased with acute starvation, and total GDF-15 increased with chronic energy deprivation, compared with healthy subjects and regardless of leptin repletion. Baseline GDF-15 positively correlated with triglyceride-rich particles and lipoproteins. During acute metabolic stress, GDF-15 associations with metabolites/lipids appeared to differ in subjects with the H202D-variant. Our findings suggest GDF-15 increases with energy deprivation in humans, questioning its proposed weight loss and suggesting its function as a mitokine, reflecting or mediating metabolic stress response.
    DOI:  https://doi.org/10.1038/s41467-024-49366-y
  4. Cell Rep. 2024 Jun 17. pii: S2211-1247(24)00707-1. [Epub ahead of print]43(7): 114379
    The PP2A regulatory subunit PPP2R2A controls NAD+ biosynthesis to regulate T cell subset differentiation in systemic autoimmunity.
    Wenliang Pan, Maria G Tsokos, Marc Scherlinger, Wei Li, George C Tsokos.
      The protein phosphatase 2A (PP2A) regulatory subunit PPP2R2A is involved in the regulation of immune response. We report that lupus-prone mice with T cells deficient in PPP2R2A display less autoimmunity and nephritis. PPP2R2A deficiency promotes NAD+ biosynthesis through the nicotinamide riboside (NR)-directed salvage pathway in T cells. NR inhibits murine Th17 and promotes Treg cell differentiation, in vitro, by PΑRylating histone H1.2 and causing its reduced occupancy in the Foxp3 loci and increased occupancy in the Il17a loci, leading to increased Foxp3 and decreased Il17a transcription. NR treatment suppresses disease in MRL.lpr mice and restores NAD+-dependent poly [ADP-ribose] polymerase 1 (PARP1) activity in CD4 T cells from patients with systemic lupus erythematosus (SLE), while reducing interferon (IFN)-γ and interleukin (IL)-17 production. We conclude that PPP2R2A controls the level of NAD+ through the NR-directed salvage pathway and promotes systemic autoimmunity. Translationally, NR suppresses lupus nephritis in mice and limits the production of proinflammatory cytokines by SLE T cells.
    Keywords:  CP: Immunology; CP: Metabolism; NAD(+); NR; PARP1; PP2A; PPP2R2A; Th17; Treg; histone H1.2; systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.celrep.2024.114379
  5. Metabolism. 2024 Jun 19. pii: S0026-0495(24)00179-3. [Epub ahead of print] 155952
    The lipopolysaccharide-TLR4 axis regulates hepatic glutaminase 1 expression promoting liver ammonia build-up as steatotic liver disease progresses to steatohepatitis.
    Maria Mercado-Gómez, Naroa Goikoetxea-Usandizaga, Annarein J C Kerbert, Leire Uraga Gracianteparaluceta, Marina Serrano-Maciá, Sofia Lachiondo-Ortega, Rubén Rodriguez-Agudo, Clàudia Gil-Pitarch, Jorge Simón, Irene González-Recio, Marcos F Fondevila, Pablo Santamarina-Ojeda, Mario F Fraga, Rubén Nogueiras, Javier de Las Heras, Rajiv Jalan, María Luz Martínez-Chantar, Teresa C Delgado.
       INTRODUCTION: Ammonia is a pathogenic factor implicated in the progression of metabolic-associated steatotic liver disease (MASLD). The contribution of the glutaminase 1 (GLS) isoform, an enzyme converting glutamine to glutamate and ammonia, to hepatic ammonia build-up and the mechanisms underlying its upregulation in metabolic-associated steatohepatitis (MASH) remain elusive.
    METHODS: Multiplex transcriptomics and targeted metabolomics analysis of liver biopsies in dietary mouse models representing the whole spectra of MASLD were carried out to characterize the relevance of hepatic GLS during disease pathological progression. In addition, the acute effect of liver-specific GLS inhibition in hepatic ammonia content was evaluated in cultured hepatocytes and in in vivo mouse models of diet-induced MASLD. Finally, the regulatory mechanisms of hepatic GLS overexpression related to the lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4) axis were explored in the context of MASH.
    RESULTS: In mouse models of diet-induced MASLD, we found that augmented liver GLS expression is closely associated with the build-up of hepatic ammonia as the disease progresses from steatosis to steatohepatitis. Importantly, the acute silencing/pharmacological inhibition of GLS diminishes the ammonia burden in cultured primary mouse hepatocytes undergoing dedifferentiation, in steatotic hepatocytes, and in a mouse model of diet-induced steatohepatitis, irrespective of changes in ureagenesis and gut permeability. Under these conditions, GLS upregulation in the liver correlates positively with the hepatic expression of TLR4 that recognizes LPS. In agreement, the pharmacological inhibition of TLR4 reduces GLS and hepatic ammonia content in LPS-stimulated mouse hepatocytes and hyperammonemia animal models of endotoxemia.
    CONCLUSIONS: Overall, our results suggest that the LPS/TLR4 axis regulates hepatic GLS expression promoting liver ammonia build-up as steatotic liver disease progresses to steatohepatitis.
    Keywords:  Ammonia; Glutaminase; Lipopolysaccharide; Metabolic-associated steatotic liver disease; Toll-like receptor 4; Urea cycle
    DOI:  https://doi.org/10.1016/j.metabol.2024.155952
  6. Hepatology. 2024 Jun 18.
    Exploring the role of macrophages in the pathogenesis of Alcohol-associated liver disease.
    Prakash Ramachandran, Frank Tacke.
      
    DOI:  https://doi.org/10.1097/HEP.0000000000000976
  7. Adv Sci (Weinh). 2024 Jun 17. e2400437
    SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit.
    Yuan Li, Min-Hyun Kim, Lin Jiang, Lorelei Baron, Latrice D Faulkner, David P Olson, Xingyu Li, Noam Gannot, Peng Li, Liangyou Rui.
      SH2B1 mutations are associated with obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) in humans. Global deletion of Sh2b1 results in severe obesity, type 2 diabetes, and MASLD in mice. Neuron-specific restoration of SH2B1 rescues the obesity phenotype of Sh2b1-null mice, indicating that the brain is a main SH2B1 target. However, SH2B1 neurocircuits remain elusive. SH2B1-expressing neurons in the paraventricular hypothalamus (PVHSH2B1) and a PVHSH2B1→dorsal raphe nucleus (DRN) neurocircuit are identified here. PVHSH2B1 axons monosynaptically innervate DRN neurons. Optogenetic stimulation of PVHSH2B1 axonal fibers in the DRN suppresses food intake. Chronic inhibition of PVHSH2B1 neurons causes obesity. In male and female mice, either embryonic-onset or adult-onset deletion of Sh2b1 in PVH neurons causes energy imbalance, obesity, insulin resistance, glucose intolerance, and MASLD. Ablation of Sh2b1 in the DRN-projecting PVHSH2B1 subpopulation also causes energy imbalance, obesity, and metabolic disorders. Conversely, SH2B1 overexpression in either total or DRN-projecting PVHSH2B1 neurons protects against diet-induced obesity. SH2B1 binds to TrkB and enhances brain-derived neurotrophic factor (BDNF) signaling. Ablation of Sh2b1 in PVHSH2B1 neurons induces BDNF resistance in the PVH, contributing to obesity. In conclusion, these results unveil a previously unrecognized PVHSH2B1→DRN neurocircuit through which SH2B1 defends against obesity by enhancing BDNF/TrkB signaling.
    Keywords:  BDNF TrkB; SH2B1; dorsal raphe nucleus; energy balance; food intake; insulin leptin; obesity, paraventricular hypothalamus
    DOI:  https://doi.org/10.1002/advs.202400437
  8. Metabolism. 2024 Jun 13. pii: S0026-0495(24)00167-7. [Epub ahead of print] 155940
    Hepatic noradrenergic innervation acts via CREB/CRTC2 to activate gluconeogenesis during cold.
    Henrique J N Morgan, Heitor B P Delfino, Aline Z Schavinski, Samuel A Malone, Camille Charoy, Natany G Reis, Ana P Assis, Natalia Lautherbach, Wilian A Silveira, Lilian C Heck, Dan Guton, Ana I Domingos, Isis C Kettelhut, Marc Montminy, Luiz C C Navegantes.
       BACKGROUND AND AIM: Although it is well established that hormones like glucagon stimulates gluconeogenesis via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2, the role of neural signals in the regulation of gluconeogenesis remains uncertain.
    METHODS AND RESULTS: Here, we characterize the noradrenergic bundle architecture in mouse liver; we show that the sympathoexcitation induced by acute cold exposure promotes hyperglycemia and upregulation of gluconeogenesis via triggering of the CREB/CRTC2 pathway. Following its induction by dephosphorylation, CRTC2 translocates to the nucleus and drives the transcription of key gluconeogenic genes. Rodents submitted to different models of sympathectomy or knockout of CRTC2 do not activate gluconeogenesis in response to cold. Norepinephrine directly acts in hepatocytes mainly through a Ca2+-dependent pathway that stimulates CREB/CRTC2, leading to activation of the gluconeogenic program.
    CONCLUSION: Our data demonstrate the importance of the CREB/CRTC2 pathway in mediating effects of hepatic sympathetic inputs on glucose homeostasis, providing new insights into the role of norepinephrine in health and disease.
    Keywords:  Calcium pathway; Hepatic glucose production; Liver; Noradrenaline; Sympathetic nervous system
    DOI:  https://doi.org/10.1016/j.metabol.2024.155940
  9. Nat Metab. 2024 Jun 21.
    The sphingosine-1-phosphate receptor 1 mediates the atheroprotective effect of eicosapentaenoic acid.
    Ting Zhou, Jie Cheng, Shuo He, Chao Zhang, Ming-Xin Gao, Li-Jun Zhang, Jin-Peng Sun, Yi Zhu, Ding Ai.
      Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been associated with potential cardiovascular benefits, partly attributed to their bioactive metabolites. However, the underlying mechanisms responsible for these advantages are not fully understood. We previously reported that metabolites of the cytochrome P450 pathway derived from eicosapentaenoic acid (EPA) mediated the atheroprotective effect of ω-3 PUFAs. Here, we show that 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and its receptor, sphingosine-1-phosphate receptor 1 (S1PR1), in endothelial cells (ECs) can inhibit oscillatory shear stress- or tumor necrosis factor-α-induced endothelial activation in cultured human ECs. Notably, the atheroprotective effect of 17,18-EEQ and purified EPA is circumvented in male mice with endothelial S1PR1 deficiency. Mechanistically, the anti-inflammatory effect of 17,18-EEQ relies on calcium release-mediated endothelial nitric oxide synthase (eNOS) activation, which is abolished upon inhibition of S1PR1 or Gq signaling. Furthermore, 17,18-EEQ allosterically regulates the conformation of S1PR1 through a polar interaction with Lys34Nter. Finally, we show that Vascepa, a prescription drug containing highly purified and stable EPA ethyl ester, exerts its cardiovascular protective effect through the 17,18-EEQ-S1PR1 pathway in male and female mice. Collectively, our findings indicate that the anti-inflammatory effect of 17,18-EEQ involves the activation of the S1PR1-Gq-Ca2+-eNOS axis in ECs, offering a potential therapeutic target against atherosclerosis.
    DOI:  https://doi.org/10.1038/s42255-024-01070-3
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