bims-obesme 2024-04-07 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024–04–07
eightteen papers selected by
Xiong Weng, University of Edinburgh

Forged in the Fire: Lasting Impacts of Inflammation on Hematopoietic Progenitors.
High-fat diets promote peritoneal inflammation and augment endometriosis-associated abdominal hyperalgesia.
Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis.
Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1.
Involution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway.
Anti-inflammatory Effects of Food Ingredients on Mice Adipose Tissues and Adipocytes.
Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss.
TAK1-binding proteins (TAB)2 and TAB3 are redundantly required for TLR-induced cytokine production in macrophages.
The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation.
JAK/STAT mediated insulin resistance in muscles is essential for effective immune response.
Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.
The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages.
Glycogen synthesis is required for adaptive thermogenesis in beige adipose tissue and affects diet-induced obesity.
TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction.
A PTER-dependent pathway of taurine metabolism linked to energy balance.
Repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition.
IL-33-ST2 signaling in fibro-adipogenic progenitors alleviates immobilization-induced muscle atrophy in mice.
Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.

Exp Hematol. 2024 Apr 03. pii: S0301-472X(24)00074-2. [Epub ahead of print] 104215

Forged in the Fire: Lasting Impacts of Inflammation on Hematopoietic Progenitors.

Ruoqiong Cao, Apoorva Thatavarty, Katherine Y King.

  Quiescence and differentiation of hematopoietic stem and progenitor cells (HSPC) can be modified by systemic inflammatory cues. Such cues can not only yield short term changes in HSPCs such as in supporting emergency granulopoiesis but can also promote lasting influences on the HSPC compartment. First, inflammation can be a driver for clonal expansion, promoting clonal hematopoiesis for certain mutant clones, reducing overall clonal diversity, and reshaping the composition of the HSPC pool with significant health consequences. Second, inflammation can generate lasting cell-autonomous changes in HSPCs themselves, leading to changes in the epigenetic state, metabolism, and the function of downstream innate immune cells. This concept, termed "trained immunity," suggests that inflammatory stimuli can alter subsequent immune responses leading to improved innate immunity or, conversely, autoimmunity. Both of these concepts have major implications in human health. Here we review current literature about the lasting effects of inflammation on the HSPC compartment and opportunities for future advancement in this fast-developing field.

Keywords:  Clonal Hematopoiesis; Hematopoiesis; epigenetics; inflammation; metabolism; trained immunity

DOI:  https://doi.org/10.1016/j.exphem.2024.104215
Front Endocrinol (Lausanne). 2024 ;15 1336496

High-fat diets promote peritoneal inflammation and augment endometriosis-associated abdominal hyperalgesia.

Tristin Herup-Wheeler, Mingxin Shi, Madeleine E Harvey, Chandni Talwar, Ramakrishna Kommagani, James A MacLean, Kanako Hayashi.

  Immune dysfunction is one of the central components in the development and progression of endometriosis by establishing a chronic inflammatory environment. Western-style high-fat diets (HFD) have been linked to greater systemic inflammation to cause metabolic and chronic inflammatory diseases, and are also considered an environmental risk factor for gynecologic diseases. Here, we aimed to examine how HFD cause an inflammatory environment in endometriosis and discern their contribution to endometriotic-associated hyperalgesia. Our results showed that HFD-induced obesity enhanced abdominal hyperalgesia that was induced by endometriotic lesions. Peritoneal inflammatory macrophages and cytokine levels increased by lesion induction were elevated by chronic exposure to HFD. Increased expression of pain-related mediators in the dorsal root ganglia was observed after lesion induction under the HFD condition. Although HFD did not affect inflammatory macrophages in the peritoneal cavity without lesion induction, the diversity and composition of the gut microbiota were clearly altered by HFD as a sign of low-grade systemic inflammation. Thus, HFD alone might not establish a local inflammatory environment in the pelvic cavity, but it can contribute to further enhancing chronic inflammation, leading to the exacerbation of endometriosis-associated abdominal hyperalgesia following the establishment and progression of the disease.

Keywords:  endometriosis; high-fat diets; inflammation; macrophages; microbiota; pain

DOI:  https://doi.org/10.3389/fendo.2024.1336496
Elife. 2024 Apr 02. pii: RP89136. [Epub ahead of print]12

Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis.

Kyounghee Min, Batuhan Yenilmez, Mark Kelly, Dimas Echeverria, Michael Elleby, Lawrence M Lifshitz, Naideline Raymond, Emmanouela Tsagkaraki, Shauna M Harney, Chloe DiMarzio, Hui Wang, Nicholas McHugh, Brianna Bramato, Brett Morrison, Jeffery D Rothstein, Anastasia Khvorova, Michael P Czech.

  Circulating lactate is a fuel source for liver metabolism but may exacerbate metabolic diseases such as nonalcoholic steatohepatitis (NASH). Indeed, haploinsufficiency of lactate transporter monocarboxylate transporter 1 (MCT1) in mice reportedly promotes resistance to hepatic steatosis and inflammation. Here, we used adeno-associated virus (AAV) vectors to deliver thyroxin binding globulin (TBG)-Cre or lecithin-retinol acyltransferase (Lrat)-Cre to MCT1fl/fl mice on a choline-deficient, high-fat NASH diet to deplete hepatocyte or stellate cell MCT1, respectively. Stellate cell MCT1KO (AAV-Lrat-Cre) attenuated liver type 1 collagen protein expression and caused a downward trend in trichrome staining. MCT1 depletion in cultured human LX2 stellate cells also diminished collagen 1 protein expression. Tetra-ethylenglycol-cholesterol (Chol)-conjugated siRNAs, which enter all hepatic cell types, and hepatocyte-selective tri-N-acetyl galactosamine (GN)-conjugated siRNAs were then used to evaluate MCT1 function in a genetically obese NASH mouse model. MCT1 silencing by Chol-siRNA decreased liver collagen 1 levels, while hepatocyte-selective MCT1 depletion by AAV-TBG-Cre or by GN-siRNA unexpectedly increased collagen 1 and total fibrosis without effect on triglyceride accumulation. These findings demonstrate that stellate cell lactate transporter MCT1 significantly contributes to liver fibrosis through increased collagen 1 protein expression in vitro and in vivo, while hepatocyte MCT1 appears not to be an attractive therapeutic target for NASH.

Keywords:  AAV; NAFLD; NASH; RNAi therapeutics; cell biology; human; liver fibrosis; mouse; stellate cells

DOI:  https://doi.org/10.7554/eLife.89136
Elife. 2024 Apr 03. pii: RP89270. [Epub ahead of print]12

Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1.

Ayse Kilic, Arda Halu, Margherita De Marzio, Enrico Maiorino, Melody G Duvall, Thayse Regina Bruggemann, Joselyn J Rojas Quintero, Robert Chase, Hooman Mirzakhani, Ayse Özge Sungur, Janine Koepke, Taiji Nakano, Hong Yong Peh, Nandini Krishnamoorthy, Raja-Elie Abdulnour, Katia Georgopoulos, Augusto A Litonjua, Marie Demay, Harald Renz, Bruce D Levy, Scott T Weiss.

  Vitamin D possesses immunomodulatory functions and vitamin D deficiency has been associated with the rise in chronic inflammatory diseases, including asthma (Litonjua and Weiss, 2007). Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D-mediated immunoregulation. Here, we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases. We demonstrate increased vitamin D receptor (Vdr) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long-term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of the Ikzf3-encoded protein Aiolos to suppress IL-2 signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders.

Keywords:  asthma; genetics; genomics; human; immunology; inflammation; mouse; vitamin D receptor

DOI:  https://doi.org/10.7554/eLife.89270
Nat Commun. 2024 Apr 02. 15(1): 2856

Involution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway.

Xiaofan Yu, Gabrielle Benitez, Peter Tszki Wei, Sofia V Krylova, Ziyi Song, Li Liu, Meifan Zhang, Alus M Xiaoli, Henna Wei, Fenfen Chen, Simone Sidoli, Fajun Yang, Kosaku Shinoda, Jeffrey E Pessin, Daorong Feng.

Aging, chronic high-fat diet feeding, or housing at thermoneutrality induces brown adipose tissue (BAT) involution, a process characterized by reduction of BAT mass and function with increased lipid droplet size. Single nuclei RNA sequencing of aged mice identifies a specific brown adipocyte population of Ucp1-low cells that are pyroptotic and display a reduction in the longevity gene syntaxin 4 (Stx4a). Similar to aged brown adipocytes, Ucp1-STX4KO mice display loss of brown adipose tissue mass and thermogenic dysfunction concomitant with increased pyroptosis. Restoration of STX4 expression or suppression of pyroptosis activation protects against the decline in both mass and thermogenic activity in the aged and Ucp1-STX4KO mice. Mechanistically, STX4 deficiency reduces oxidative phosphorylation, glucose uptake, and glycolysis leading to reduced ATP levels, a known triggering signal for pyroptosis. Together, these data demonstrate an understanding of rapid brown adipocyte involution and that physiologic aging and thermogenic dysfunction result from pyroptotic signaling activation.

DOI: https://doi.org/10.1038/s41467-024-46944-y
J Oleo Sci. 2024 ;73(4): 411-418

Anti-inflammatory Effects of Food Ingredients on Mice Adipose Tissues and Adipocytes.

Chikako Kiyose.

  In 2021, we published three papers related to the anti-inflammatory effects of food ingredients. The present paper reports the effects of vitamin E homologs and sweet basil powder. In these papers, we investigated whether inflammation occurs in the adipose tissue of mice fed a high-fat and high-sucrose diet for 16 weeks. Inflammatory cytokine gene expression was significantly higher in the epididymal fat of the high-fat and high-sucrose diet group than in that of the control diet group. However, the addition of α-tocopherol or δ-tocopherol to the diet could not restrain the inflammation of mice epididymal fats. Thereafter, we investigated the anti-inflammatory effects of α- and δ-tocopherols using the co-cultured cells. Consequently, we clarified that δ-tocopherol inhibited the increase in the gene expressions of inflammatory cytokines. We also examined the effect of sweet basil powder on a similar obese mice model. The final body weight in the high-fat and high-sucrose group that received sweet basil powder was significantly lower than that in the high-fat and high-sucrose diet group. Liver weights were also significantly lower in the high-fat and high-sucrose diet group that received sweet basil powder than in the high-fat and high-sucrose diet group, although adipose tissue weights were unchanged in both groups. Furthermore, sweet basil powder tended to inhibit in lipid synthesis in the mice livers. Therefore, we suggested that sweet basil powder inhibited fatty acid synthesis in mice livers, thereby suppressing liver enlargement, and resulting in body weight loss. Moreover, the gene expression of MCP-1 in the adipose tissue of mice fed a high-fat and high-sucrose diet added with sweet basil powder was significantly lower than that of mice fed a high-fat and high-sucrose diet for 12 weeks. Therefore, sweet basil powder inhibited inflammation onset in the adipose tissue of mice. Taken together, the results suggested that food ingredients, especially vitamin E homologs and sweet basil powder, have anti-inflammatory effects on mice adipose tissue and mice adipocyte-induced inflammation.

Keywords:  adipose tissue; anti-inflammation; anti-obesity; sweet bail; tocopherol

DOI:  https://doi.org/10.5650/jos.ess23221
Cell Metab. 2024 Apr 02. pii: S1550-4131(24)00053-6. [Epub ahead of print]36(4): 857-876.e10

Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss.

Dongxian Guan, Yuqin Men, Alexander Bartlett, Mario Andrés Salazar Hernández, Jie Xu, Xinchi Yi, Hu-Song Li, Dong Kong, Ralph Mazitschek, Umut Ozcan.

  Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter's activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizers and anti-obesity agents.

Keywords:  HDAC6 inhibitors; acetylation; anti-obesity drug; leptin receptor; leptin resistance; obesity; obesity treatment; translational medicine; type 2 diabetes

DOI:  https://doi.org/10.1016/j.cmet.2024.02.007
Int Immunol. 2024 Apr 03. pii: dxae020. [Epub ahead of print]

TAK1-binding proteins (TAB)2 and TAB3 are redundantly required for TLR-induced cytokine production in macrophages.

Tanveer Ali, Huong Minh Nguyen, Naeem Abbas, Osamu Takeuchi, Shizuo Akira, Toshihiko Suzuki, Goro Matsuzaki, Giichi Takaesu.

  Transforming growth factor-β-activated kinase 1 (TAK1) plays a pivotal role in innate and adaptive immunity. TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways downstream of diverse immune receptors, including Toll-like receptors (TLRs). Upon stimulation with TLR ligands, TAK1 is activated via recruitment to lysine 63-linked polyubiquitin chain through TAK1-binding proteins (TAB) 2 and TAB3. However, the physiological importance of TAB2 and TAB3 in macrophages is still controversial. A previous study has shown that mouse bone marrow-derived macrophages (BMDMs) isolated from mice double deficient for TAB2 and TAB3 produced tumor necrosis factor (TNF)-α and interleukin (IL)-6 to the similar levels as control wild-type BMDMs in response to TLR ligands such as lipopolysaccharide (LPS) or Pam3CSK4, indicating that TAB2 and TAB3 are dispensable for TLR signaling. In this study, we revisited the role of TAB2 and TAB3 using an improved mouse model. We observed a significant impairment in the production of pro-inflammatory cytokines and chemokine in LPS- or Pam3CSK4-treated BMDMs deficient for both TAB2 and TAB3. Double deficiency of TAB2 and TAB3 resulted in the decreased activation of NF-κB and MAPK pathways as well as the slight decrease in TAK1 activation in response to LPS or Pam3CSK4. Notably, the TLR-mediated expression of inhibitor of NF-κB (IκB)ζ was severely compromised at the protein and mRNA levels in the TAB2/TAB3 double-deficient BMDMs, thereby impeding IL-6 production. Our results suggest that TAB2 and TAB3 play a redundant and indispensable role in TLR signaling pathway.

Keywords:  LysM-Cre; Macrophages; TAK1-binding proteins; TLR; signal transduction

DOI:  https://doi.org/10.1093/intimm/dxae020
Sci Signal. 2024 Apr 02. 17(830): eade4335

The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation.

Manuel A Fernandez-Rojo, Michael A Pearen, Anita G Burgess, Maria P Ikonomopoulou, Diem Hoang-Le, Berit Genz, Silvia L Saggiomo, Sujeevi S K Nawaratna, Maura Poli, Regina Reissmann, Geoffrey N Gobert, Urban Deutsch, Britta Engelhardt, Andrew J Brooks, Alun Jones, Paolo Arosio, Grant A Ramm.

Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby the heavy subunit of ferritin (FTH) contributes to hepatic inflammation. We found that FTH induced activation of the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin-1β (IL-1β) in primary rat hepatic stellate cells (HSCs) through intercellular adhesion molecule-1 (ICAM-1). FTH-ICAM-1 stimulated the expression of Il1b, NLRP3 inflammasome activation, and the processing and secretion of IL-1β in a manner that depended on plasma membrane remodeling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH-ICAM-1 signaling at early endosomes stimulated Il1b expression, implying that this endosomal signaling primed inflammasome activation in HSCs. In contrast, lysosomal destabilization was required for FTH-induced IL-1β secretion, suggesting that lysosomal damage activated inflammasomes. FTH induced IL-1β production in liver slices from wild-type mice but not in those from Icam1-/- or Nlrp3-/- mice. Thus, FTH signals through its receptor ICAM-1 on HSCs to activate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key process that stimulates hepatic fibrogenesis associated with chronic liver disease.

DOI: https://doi.org/10.1126/scisignal.ade4335
Cell Commun Signal. 2024 Apr 02. 22(1): 203

JAK/STAT mediated insulin resistance in muscles is essential for effective immune response.

Ellen McMullen, Lukas Strych, Lenka Chodakova, Amber Krebs, Tomas Dolezal.

   BACKGROUND: The metabolically demanding nature of immune response requires nutrients to be preferentially directed towards the immune system at the expense of peripheral tissues. We study the mechanisms by which this metabolic reprograming occurs using the parasitoid infection of Drosophila larvae. To overcome such an immune challenge hemocytes differentiate into lamellocytes, which encapsulate and melanize the parasitoid egg. Hemocytes acquire the energy for this process by expressing JAK/STAT ligands upd2 and upd3, which activates JAK/STAT signaling in muscles and redirects carbohydrates away from muscles in favor of immune cells.
METHODS: Immune response of Drosophila larvae was induced by parasitoid wasp infestation. Carbohydrate levels, larval locomotion and gene expression of key proteins were compared between control and infected animals. Efficacy of lamellocyte production and resistance to wasp infection was observed for RNAi and mutant animals.
RESULTS: Absence of upd/JAK/STAT signaling leads to an impaired immune response and increased mortality. We demonstrate how JAK/STAT signaling in muscles leads to suppression of insulin signaling through activation of ImpL2, the inhibitor of Drosophila insulin like peptides.
CONCLUSIONS: Our findings reveal cross-talk between immune cells and muscles mediates a metabolic shift, redirecting carbohydrates towards immune cells. We emphasize the crucial function of muscles during immune response and show the benefits of insulin resistance as an adaptive mechanism that is necessary for survival.

Keywords:   Drosophila ; Immunity; Insulin resistance; JAK/STAT signaling; Metabolism

DOI:  https://doi.org/10.1186/s12964-024-01575-0
J Neuroinflammation. 2024 Apr 02. 21(1): 81

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.

Min Wang, Tian Tian, Hong Zhou, Si-Yuan Jiang, Ying-Ying Jiao, Zhu Zhu, Jiang Xia, Jian-Hua Ma, Ren-Hong Du.

   BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined.
METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD.
RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration.
CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

Keywords:  Astrocyte senescence; Metformin; Mitofusin 2; Parkinson’s disease; cGAS-STING

DOI:  https://doi.org/10.1186/s12974-024-03072-0
Discov Immunol. 2023 ;2(1): kyad027

The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages.

Sally A Clayton, Chloe Lockwood, John D O'Neil, Kalbinder K Daley, Sofia Hain, Dina Abdelmottaleb, Oliwia O Bolimowska, Daniel A Tennant, Andrew R Clark.

  Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis caused by changes in glucose traffic and metabolism in muscle, liver, and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to support various pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly used model systems (mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhibited lipopolysaccharide-mediated activation of the hypoxia-inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types, dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobic glycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human and mouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptake in activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanistic basis, depending on the alteration of glucose utilization.

Keywords:  GLUT1; HIF-1α; glucocorticoid; glycolysis; inflammation; macrophage

DOI:  https://doi.org/10.1093/discim/kyad027
Am J Physiol Endocrinol Metab. 2024 Apr 03.

Glycogen synthesis is required for adaptive thermogenesis in beige adipose tissue and affects diet-induced obesity.

Shixuan Zhuo, Meijuan Bai, Zinan Wang, Lingling Chen, Zixuan Li, Jinzhu Chen, Xiaoyi Ye, Cheng Guo, Yan Chen.

  Glycogen is a form of energy storage for glucose in different tissues such as liver and skeletal muscle. It remains incompletely understood how glycogen impacts on adipose tissue functionality. Cold exposure elevated the expression of Gys1 which encodes glycogen synthase 1 in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). The in vivo function of Gys1 was analyzed using a mouse model in which Gys1 was deleted specifically in adipose tissues. Under normal chow conditions, Gys1 deletion caused little changes to body weight and glucose metabolism. Deletion of Gys1 abrogated upregulation of UCP1 and other thermogenesis-related genes in iWAT upon prolonged cold exposure or treatment with b3-adrenergic receptor agonist CL-316,243. Stimulation of UCP1 by CL-316,243 in adipose-derived stromal cells (SVFs) was also reduced by Gys1 deletion. Both the basal glycogen content and CL-316,243-stimulated glycogen accumulation in adipose tissues were reduced by Gys1 deletion. High-fat diet-induced obesity and insulin resistance were aggravated in Gys1-deleted mice. The loss of body weight upon CL-316,243 treatment was also abrogated by the loss of Gys1. In conclusion, our results underscore the pivotal role of glycogen synthesis in adaptive thermogenesis in beige adipose tissue and its impact on diet-induced obesity in mice.

Keywords:  adipose tissue; glycogen; obesity; thermogenesis

DOI:  https://doi.org/10.1152/ajpendo.00074.2024
Nat Commun. 2024 Mar 30. 15(1): 2779

TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction.

Cheoljun Choi, Yujin L Jeong, Koung-Min Park, Minji Kim, Sangseob Kim, Honghyun Jo, Sumin Lee, Heeseong Kim, Garam Choi, Yoon Ha Choi, Je Kyung Seong, Sik Namgoong, Yeonseok Chung, Young-Suk Jung, James G Granneman, Young-Min Hyun, Jong Kyoung Kim, Yun-Hee Lee.

Adipose tissue (AT) adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Among immune cells recruited to AT, lipid-associated macrophages (LAMs) have emerged as key players in obesity and in diseases involving lipid stress and inflammation. Here, we show that LAMs selectively express transmembrane 4 L six family member 19 (TM4SF19), a lysosomal protein that represses acidification through its interaction with Vacuolar-ATPase. Inactivation of TM4SF19 elevates lysosomal acidification and accelerates the clearance of dying/dead adipocytes in vitro and in vivo. TM4SF19 deletion reduces the LAM accumulation and increases the proportion of restorative macrophages in AT of male mice fed a high-fat diet. Importantly, male mice lacking TM4SF19 adapt to high-fat feeding through adipocyte hyperplasia, rather than hypertrophy. This adaptation significantly improves local and systemic insulin sensitivity, and energy expenditure, offering a potential avenue to combat obesity-related metabolic dysfunction.

DOI: https://doi.org/10.1038/s41467-024-47108-8
bioRxiv. 2024 Mar 22. pii: 2024.03.21.586194. [Epub ahead of print]

A PTER-dependent pathway of taurine metabolism linked to energy balance.

Wei Wei, Xuchao Lyu, Andrew L Markhard, Sipei Fu, Rachel E Mardjuki, Peter E Cavanagh, Xianfeng Zeng, Jakub Rajniak, Nannan Lu, Shuke Xiao, Meng Zhao, Maria Dolores Moya-Garzon, Steven D Truong, Jonathan Chiu-Chun Chou, Lianna W Wat, Saranya Chidambaranathan-Reghupaty, Laetitia Coassolo, Duo Xu, Fangfang Shen, Wentao Huang, Cuauhtemoc B Ramirez, Cholsoon Jang, Katrin J Svensson, Michael A Fischbach, Jonathan Z Long.

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans 1-3 . In endogenous taurine metabolism, dedicated enzymes are involved in biosynthesis of taurine from cysteine as well as the downstream derivatization of taurine into secondary taurine metabolites 4,5 . One such taurine metabolite is N-acetyltaurine 6 . Levels of N-acetyltaurine are dynamically regulated by diverse physiologic perturbations that alter taurine and/or acetate flux, including endurance exercise 7 , nutritional taurine supplementation 8 , and alcohol consumption 6,9 . While taurine N-acetyltransferase activity has been previously detected in mammalian cells 6,7 , the molecular identity of this enzyme, and the physiologic relevance of N-acetyltaurine, have remained unknown. Here we show that the orphan body mass index-associated enzyme PTER (phosphotriesterase-related) 10 is the principal mammalian taurine N-acetyltransferase/hydrolase. In vitro, recombinant PTER catalyzes bidirectional taurine N-acetylation with free acetate as well as the reverse N-acetyltaurine hydrolysis reaction. Genetic ablation of PTER in mice results in complete loss of tissue taurine N-acetyltransferase/hydrolysis activities and systemic elevation of N-acetyltaurine levels. Upon stimuli that increase taurine levels, PTER-KO mice exhibit lower body weight, reduced adiposity, and improved glucose homeostasis. These phenotypes are recapitulated by administration of N-acetyltaurine to wild-type mice. Lastly, the anorexigenic and anti-obesity effects of N-acetyltaurine require functional GFRAL receptors. Together, these data uncover enzymatic control of a previously enigmatic pathway of secondary taurine metabolism linked to energy balance.

DOI: https://doi.org/10.1101/2024.03.21.586194
Acta Pharm Sin B. 2024 Apr;14(4): 1711-1725

Repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition.

Yingting Wu, Jiaqi Xin, Xinyu Li, Ting Yang, Yi Liu, Yongsheng Zhao, Wen Xie, Mengxi Jiang.

  Drug repurposing offers an efficient approach to therapeutic development. In this study, our bioinformatic analysis first predicted an association between obesity and lansoprazole (LPZ), a commonly prescribed drug for gastrointestinal ulcers. We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity, insulin resistance, and hepatic steatosis in mice. Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes, and induced cold tolerance in cold-exposed mice, suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism. Mechanistically, LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1 (PHOSPHO1) and produces metabolic benefits in a PHOSPHO1-dependent manner. Our results suggested that LPZ may stimulate adipose thermogenesis by inhibiting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid (2-AG-LPA) to 2-arachidonoylglycerol (2-AG) and reduce the activity of the thermogenic-suppressive cannabinoid receptor signaling. In summary, we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome, and identified a potential metabolic basis by which LPZ improves energy metabolism.

Keywords:  Adipose thermogenesis; Cannabinoid receptor signaling; Drug repurposing; Energy expenditure; Lansoprazole; Metabolic syndrome; PHOSPHO1 inhibitor; Proton pump inhibitors

DOI:  https://doi.org/10.1016/j.apsb.2024.01.001
Skelet Muscle. 2024 Apr 01. 14(1): 6

IL-33-ST2 signaling in fibro-adipogenic progenitors alleviates immobilization-induced muscle atrophy in mice.

Yoshiyuki Takahashi, Masaki Yoda, Osahiko Tsuji, Keisuke Horiuchi, Kota Watanabe, Masaya Nakamura.

   BACKGROUND: The regenerative and adaptive capacity of skeletal muscles reduces with age, leading to severe disability and frailty in the elderly. Therefore, development of effective therapeutic interventions for muscle wasting is important both medically and socioeconomically. In the present study, we aimed to elucidate the potential contribution of fibro-adipogenic progenitors (FAPs), which are mesenchymal stem cells in skeletal muscles, to immobilization-induced muscle atrophy.
METHODS: Young (2-3 months), adult (12-14 months), and aged (20-22 months) mice were used for analysis. Muscle atrophy was induced by immobilizing the hind limbs with a steel wire. FAPs were isolated from the hind limbs on days 0, 3, and 14 after immobilization for transcriptome analysis. The expression of ST2 and IL-33 in FAPs was evaluated by flow cytometry and immunostaining, respectively. To examine the role of IL-33-ST2 signaling in vivo, we intraperitoneally administered recombinant IL-33 or soluble ST2 (sST2) twice a week throughout the 2-week immobilization period. After 2-week immobilization, the tibialis anterior muscles were harvested and the cross-sectional area of muscle fibers was evaluated.
RESULTS: The number of FAPs increased with the progression of muscle atrophy after immobilization in all age-groups. Transcriptome analysis of FAPs collected before and after immobilization revealed that Il33 and Il1rl1 transcripts, which encode the IL-33 receptor ST2, were transiently induced in young mice and, to a lesser extent, in aged mice. The number of FAPs positive for ST2 increased after immobilization in young mice. The number of ST2-positive FAPs also increased after immobilization in aged mice, but the difference from the baseline was not statistically significant. Immunostaining for IL-33 in the muscle sections revealed a significant increase in the number of FAPs expressing IL-33 after immobilization. Administration of recombinant IL-33 suppressed immobilization-induced muscle atrophy in aged mice but not in young mice.
CONCLUSIONS: Our data reveal a previously unknown protective role of IL-33-ST2 signaling against immobilization-induced muscle atrophy in FAPs and suggest that IL-33-ST2 signaling is a potential new therapeutic target for alleviating disuse muscle atrophy, particularly in older adults.

Keywords:  Cell sorting; Fibro-adipogenic progenitors; Flow cytometry; IL-33; Immobilization; Mouse; Muscle atrophy; ST2; Skeletal muscle

DOI:  https://doi.org/10.1186/s13395-024-00338-2
Sci Adv. 2024 Apr 05. 10(14): eadl0389

Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.

Zhenqi Zhou, Alice Ma, Timothy M Moore, Dane M Wolf, Nicole Yang, Peter Tran, Mayuko Segawa, Alexander R Strumwasser, Wenjuan Ren, Kai Fu, Jonathan Wanagat, Alexander M van der Bliek, Rachelle Crosbie-Watson, Marc Liesa, Linsey Stiles, Rebecca Acin-Perez, Sushil Mahata, Orian Shirihai, Mark O Goodarzi, Michal Handzlik, Christian M Metallo, David W Walker, Andrea L Hevener.

The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases.

DOI: https://doi.org/10.1126/sciadv.adl0389