Myeloid p38 activation maintains macrophage–liver crosstalk and BAT thermogenesis through IL‐12–FGF21 axis

Crespo, María Inés; Nikolić, Ivana; Mora, Alfonso; Rodrı́guez, Elena; Leiva‐Vega, Luis; Pintor-Chocano, Aranzazú; Horillo, Daniel; Hernández‐Cosido, Lourdes; Torres, Jorge; Novoa, Eva María; Nogueiras, Rubén; Medina‐Gómez, Gema; Marcos, Miguel; Leiva, Magdalena; Sabio, Guadalupe

doi:10.1002/hep.32581

Cited by 8 publications

(4 citation statements)

References 34 publications

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“…Our group has shown that the immune system regulates body weight by influencing AT thermogenesis (Crespo et al, 2023 ), and we observed higher BAT temperature in mice lacking p38 activation in T cells. To confirm these differences under thermoneutral conditions, we placed CD4-Cre and MKK3/6 CD4-KO mice at 30 °C throughout the entire HFD feeding.…”

Section: Resultssupporting

confidence: 58%

Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis

Nikolic,

Ruiz-Garrido,

Crespo

et al. 2024

EMBO Rep

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Obesity is characterized by low-grade inflammation, energy imbalance and impaired thermogenesis. The role of regulatory T cells (Treg) in inflammation-mediated maladaptive thermogenesis is not well established. Here, we find that the p38 pathway is a key regulator of T cell-mediated adipose tissue (AT) inflammation and browning. Mice with T cells specifically lacking the p38 activators MKK3/6 are protected against diet-induced obesity, leading to an improved metabolic profile, increased browning, and enhanced thermogenesis. We identify IL-35 as a driver of adipocyte thermogenic program through the ATF2/UCP1/FGF21 pathway. IL-35 limits CD8+ T cell infiltration and inflammation in AT. Interestingly, we find that IL-35 levels are reduced in visceral fat from obese patients. Mechanistically, we demonstrate that p38 controls the expression of IL-35 in human and mouse Treg cells through mTOR pathway activation. Our findings highlight p38 signaling as a molecular orchestrator of AT T cell accumulation and function.

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Section: Resultssupporting

confidence: 58%

Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis

Nikolic,

Ruiz-Garrido,

Crespo

et al. 2024

EMBO Rep

Self Cite

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“…Our findings further demonstrate that Smad2/3 or p38 inhibitors can mimic the effects induced by MSTN knockdown in brown adipocytes. Additionally, previous studies have indicated that the p38 signaling pathway can regulate the expression of Klf4 and Fgf21 (41,52). We herein addressed a pathway for Myostatin intracellular signals.…”

Section: Discussionmentioning

confidence: 99%

Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communication

Wang,

Guo,

Gao

et al. 2024

Journal of Clinical Investigation

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Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been increasing interest in its role in metabolism. In our study, we specifically knocked out MSTN in brown adipose tissue (BAT) from mice (MSTN ΔUCP1 ) and found that the mice gained more weight than did 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-ablated BAT. Further studies demonstrated that Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, whereas fibroblast growth factor 21 (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 adipocyte–derived MSTN regulated BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis.

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“…Alternative explanations may include stimulation of insulin-independent glucose uptake mechanisms and/or altered utilization of energy sources. MAP3K ASK1 is a major ROS-induced activator of p38 and JNK in cell lines and mouse models (44) and has also been linked to metabolic regulation (68)(69)(70). Other ROS-activated MAP3Ks that have been implicated in metabolic control are MLK2/3 and MAP3K4 (71,72).…”

Section: Discussionmentioning

confidence: 99%

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

Snieckute,

Ryder,

Vind

et al. 2023

Science

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The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)–activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)–generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging.

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Myeloid p38 activation maintains macrophage–liver crosstalk and BAT thermogenesis through IL‐12–FGF21 axis

Cited by 8 publications

References 34 publications

Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis

Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis

Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communication

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

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