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    Adipose tissue lipolysis is regulated by PAQR11 via altering protein stability of phosphodiesterase 4D. Huang Meiqin,Lin Yijun,Wang Lin,You Xue,Wang Shuo,Zhao Jingyu,Bai Meijuan,Li Zixuan,Chen Yan Molecular metabolism Fat storage and mobilization in adipose tissue play a central role in energy metabolism and are directly linked to the development of obesity. Upon starvation, fat is mobilized from adipose tissue by lipolysis, a process by which triglycerides are hydrolyzed to free fatty acids to be used as an energy source in skeletal muscles and other tissues. However, how lipolysis is activated by starvation is not fully known. In this study, we demonstrate that PAQR11, a member of the progesterone and AdipoQ receptor family, regulates starvation-mediated lipolysis. Paqr11-deleted mice are resistant to high-fat diet-induced obesity. Paqr11 deletion promotes lipolysis in white adipose tissue, characterized by increased phosphorylations of hormone-sensitive lipase (HSL) and perilipin 1 (PLIN1) and elevated serum levels of glycerol and free fatty acids. PKA activity and cAMP levels in white adipose tissue are also increased by Paqr11 deletion, accompanied by accelerated protein degradation of phosphodiesterase 4D (PDE4D). Mechanistically, PAQR11 decreases the interaction of PDE4D with SKP1-CUL1-FBXO2 E3 ligase complex, thus modulating the polyubiquitination/degradation of PDE4D. Fasting decreases the expression of the Paqr11 gene, and starvation-induced lipolysis in white adipose tissue is enhanced by Paqr11 deletion, while insulin-mediated suppression of lipolysis is not affected. Collectively, these results reveal that PAQR11 regulates lipolysis of adipose tissue and affects high-fat diet-induced obesity. 10.1016/j.molmet.2021.101182
    Dendritic Cell Metabolism and Function in Tumors. Giovanelli Paolo,Sandoval Tito A,Cubillos-Ruiz Juan R Trends in immunology Dendritic cells (DCs) are fundamental for the initiation and maintenance of immune responses against malignant cells. Despite the unique potential of DCs to elicit robust anticancer immunity, the tumor microenvironment poses a variety of challenges that hinder competent DC function and consequently inhibit the development of protective immune responses. Here, we discuss recent studies uncovering new molecular pathways and metabolic programs that tumors manipulate in DCs to disturb their homeostasis and evade immune control. We also examine certain state-of-the-art strategies that seek to improve DC function and elicit antitumor responses in hosts with cancer. Understanding and modulating DC metabolism and activity within tumors might help improve the efficacy of T cell-centric immunotherapies. 10.1016/j.it.2019.06.004
    Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Mao Kairui,Baptista Antonio P,Tamoutounour Samira,Zhuang Lenan,Bouladoux Nicolas,Martins Andrew J,Huang Yuefeng,Gerner Michael Y,Belkaid Yasmine,Germain Ronald N Nature The mammalian gut is colonized by numerous microorganisms collectively termed the microbiota, which have a mutually beneficial relationship with their host. Normally, the gut microbiota matures during ontogeny to a state of balanced commensalism marked by the absence of adverse inflammation. Subsets of innate lymphoid cells (ILCs) and conventional T cells are considered to have redundant functions in containment and clearance of microbial pathogens, but how these two major lymphoid-cell populations each contribute to shaping the mature commensal microbiome and help to maintain tissue homeostasis has not been determined. Here we identify, using advanced multiplex quantitative imaging methods, an extensive and persistent phosphorylated-STAT3 signature in group 3 ILCs and intestinal epithelial cells that is induced by interleukin (IL)-23 and IL-22 in mice that lack CD4 T cells. By contrast, in immune-competent mice, phosphorylated-STAT3 activation is induced only transiently by microbial colonization at weaning. This early signature is extinguished as CD4 T cell immunity develops in response to the expanding commensal burden. Physiologically, the persistent IL-22 production from group 3 ILCs that occurs in the absence of adaptive CD4 T-cell activity results in impaired host lipid metabolism by decreasing lipid transporter expression in the small bowel. These findings provide new insights into how innate and adaptive lymphocytes operate sequentially and in distinct ways during normal development to establish steady-state commensalism and tissue metabolic homeostasis. 10.1038/nature25437
    Dynamic Regulation of ME1 Phosphorylation and Acetylation Affects Lipid Metabolism and Colorectal Tumorigenesis. Zhu Yahui,Gu Li,Lin Xi,Liu Cheng,Lu Bingjun,Cui Kaisa,Zhou Feng,Zhao Qiu,Prochownik Edward V,Fan Chengpeng,Li Youjun Molecular cell PGAM5 is a mitochondrial serine/threonine phosphatase that regulates multiple metabolic pathways and contributes to tumorigenesis in a poorly understood manner. We show here that PGAM5 inhibition attenuates lipid metabolism and colorectal tumorigenesis in mice. PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. ME1 also promotes nicotinamide adenine dinucleotide phosphate (NADPH) production, lipogenesis, and colorectal cancers in which ME1 transcripts are upregulated and ME1 protein is hypophosphorylated at S336 and hyperacetylated at K337. PGAM5 and ME1 upregulation occur via direct transcriptional activation mediated by β-catenin/TCF1. Thus, the balance between PGAM5-mediated dephosphorylation of ME1 S336 and ACAT1-mediated acetylation of K337 strongly influences NADPH generation, lipid metabolism, and the susceptibility to colorectal tumorigenesis. 10.1016/j.molcel.2019.10.015