MAP/Microtubule affinity-regulating kinase 4 (Mark4) plays an important role in the regulation of microtubule organization, adipogenesis and apoptosis. However, the role of Mark4 plays in oxidative stress and inflammation are poorly understood. In this study, we found Mark4 was induced by high fat diet (HFD) while PPARγ was elevated significantly in mice adipocytes. Further analyses revealed Mark4 impaired mitochondrial oxidative respiration and increased reactive oxygen species (ROS) production. At same time, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) were greatly reduced. By treating cells with H2O2 and vitamin E (VE), Mark4 accentuated oxidative stress along with increased mRNA level of inflammatory factor interleukin-6 (IL-6) and decreased leptin mRNA. Furthermore, we found PPARγ bind to Mark4 promoter region and inhibited Mark4 expression. We showed PPARγ interacted with Mark4 and inhibited the stimulating effect of Mark4 on oxidative stress and inflammation. Finally, we demonstrated that the IKKα/NF-κB signal pathway was involved in Mark4 induced oxidative stress and inflammation, while PTDC, a special inhibitor of NF-κB signal pathway, reduced oxidative stress and inflammation. Thus, our study indicated that Mark4 was a potential drug target for treating metabolic diseases.

shown that Sirt1 is involved in regulation of inflammation response and inhibits inflammatory pathways in macrophages and dendritic cells (6, 7). In 3T3-L1 adipocytes, Sirt1 can attenuate TNF--induced insulin resistance and inflammation (3,8). Resveratrol (RES) is a natural polyphenolic compound known for its beneficial effects on energy homeostasis (9, 10). Studies have shown that RES attenuates inflammation of adipocytes and vascular endothelial cells by activating Sirt1 and inducing autophagy (11-13). However, the regulatory mechanism of RES on Sirt1 and adipose inflammation remains unclear.The Akt/mammalian target of rapamycin (mTOR) pathway plays an important role in the regulation of cellular gluconeogenesis and metabolism (14,15). mTOR is highly conserved serine/threonine kinase that is expressed in cancer cells, adipocytes, and hepatocytes, and can be directly phosphorylated by activated . During development of obesity, adipose pro-inflammatory responses are closely associated with the development of insulin resistance in adipose tissue (19,20). A recent study showed that phosphorylation of Akt in macrophages could activate mTOR signal and then led to inflammation and insulin resistance in high-fat diet (HFD)-induced obesity (21). Moreover, Pang et al. (22) reported that Sirt1 directly bound protein kinase B (Akt2) and then inhibited adipogenesis in porcine adipocytes. Busch et al. (23) also suggested that Akt was one of the main upstream stimulatory kinases that modulated by Sirt1. However, whether the interaction between Sirt1 and Akt2 can regulate adipose inflammation has not been studied.We suggested that RES would attenuate HFD-induced obesity and adipose inflammation by activating Sirt1. We found that RES promoted the interaction of Sirt1 and Akt2, and then inhibited adipose inflammation by activating the mTOR/S6K1 pathway. These findings identify a novel function of Sirt1 in the regulation of adipose inflammation Sirtuin type 1 (Sirt1) is a member of the silencing information regulator 2 (Sir2) family called sirtuins, and is wellknown for its deacetylation in regulation of gene silencing, energy homeostasis, and apoptosis (1-3). The overloaded calorie intake leads to dysfunction of adipocytes and causes obesity (4). Obesity is closely associated with chronic inflammation and characterized by abnormal cytokine production, increased acute-phase reactants, and an activated network of inflammatory signal pathways (5 Abbreviations: Akt2, protein kinase B; HFD, high-fat diet; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; mTOR, mammalian target of rapamycin; NAM, nicotinamide; RES, resveratrol; Sirt1, sirtuin type 1.

Alpha melanocyte stimulating hormone (α-MSH) and Forkhead box C2 protein (Foxc2) enhance lipolysis in multiple tissues. However, their relationship in adipose fatty acid oxidation (FAO) remains unclear. Here, we demonstrated that α-MSH and Foxc2 increased palmitate oxidation to CO2 in white (WAT) and brown adipose tissue (BAT). C/EBPβ expression was reduced by α-MSH and Foxc2. FFA level was elevated by α-MSH and pc-Foxc2 treatment along with increased FAO in white and brown adipocytes. The expression of FAO key enzymes, medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain acyl-CoA dehydrogenase (LCAD) were increased in α-MSH and pc-Foxc2 group. Combination of α-MSH and Foxc2 treatment synergistically promoted FAO through increasing the activity of CPT-1 and phosphorylation of ACC. We found C/EBPβ bind to MC5R and Foxc2 promoter regions and inhibited FAO. cAMP level was increased by α-MSH and Foxc2 individually treated or combined treatment. Furthermore, cAMP/PKA pathway-specific inhibitor (H89) blocked the FAO, despite in α-MSH and Foxc2 both added group. While forskolin, the cAMP agonist, promoted FAO and enhanced the effect of α-MSH and Foxc2. Collectively, α-MSH and Foxc2 mutual promote FAO in WAT and BAT via cAMP/PKA signal pathway. And C/EBPβ as a transcription suppressor inhibits α-MSH and Foxc2 expression and FAO.

Cyclin-dependent kinases (CDKs) are emerging regulators of adipose tissue metabolism. Here we aimed to explore the role of CDK7 in thermogenic fat. We found that CDK7 brown adipose tissue (BAT)-specific knockout mice (Cdk7 bKO ) have decreased BAT mass and impaired b3-adrenergic signaling and develop hypothermia upon cold exposure. We found that loss of CDK7 in BAT disrupts the induction of thermogenic genes in response to cold. However, Cdk7 bKO mice do not show systemic metabolic dysfunction. Increased expression of genes of the creatine metabolism compensates for the heat generation in the BAT of Cdk7 bKO mice in response to cold. Finally, we show that CDK7 is required for beta 3-adrenergic agonist-induced browning of white adipose tissue (WAT). Indeed, Cdk7 ablation in all adipose tissues (Cdk7 aKO ) has impaired browning in WAT. Together, our results demonstrate that CDK7 is an important mediator of beta-adrenergic signaling in thermogenic brown and beige fat.

Suppressor of cytokine signaling 2 (SOCS2) plays an important role in fat deposition, skeletal muscle, central nervous system development, and mitochondria biogenesis. Nevertheless, the regulatory mechanisms of SOCS2 on mitochondrial fatty acid oxidation (FAO) remain unclear. Leptin could inhibit food intake and increase thermogenesis through leptin receptor (LepR), which was present in the hypothalamus and certain peripheral organs, including adipose tissue. With strong interest, we focused on the connection between leptin and SOCS2 and their effect on FAO in adipocytes. In our study, we found that the mRNA level of SOCS2 and the protein levels of PGC-1α, CPT-1b, FAT, and p-ACC were elevated by leptin in the inguinal adipose tissue of mice. On the contrary, the protein levels of FABP4, FATP1, and FAS were declined. The genes related to fatty acid oxidation such as PGC-1α, NRF-1, TFAM, CPT-1b, AOX1, COX2, and UCP2 were attenuated by SOCS2, but elevated by leptin. Moreover, fatty acid oxidation enzyme MCAD, LCAD, and Cyt C levels were reduced in response to SOCS2. These reductions correspond well with the reduced release of free fatty acid and the reduction of mitochondrial complexes I and III by SOCS2. Furthermore, JAK2/AMPK pathway-specific inhibitors could block the mitochondrial FAO; hence, this pathway was implied to have a potential impact on FAO. Together, these studies suggested that SOCS2 had a negative effect on mitochondrial fatty acid oxidation, and the LepR/JAK2/AMPK pathway played a crucial role in this process.

Pyroptosis is a type of programmed cell death triggered by a variety of exogenous stimuli, playing important roles in the development of cells. Recent studies have shown that pyroptosis also occurs in human and mouse adipocytes. The serine/threonine protein phosphatase 1 catalytic subunit α (PP1A) is located in the nucleus and functions in the regulation of cell development, glucose metabolism and protein synthesis. PP1A can also target important proteins in the process of apoptosis. However, it is still unclear whether PP1A participates in the regulation of pyroptosis in mouse adipocytes. In the present study, we investigated the function of PP1A in reactive oxygen species‐induced pyroptosis and the related mechanism in mouse adipose tissue. Our results demonstrated that PP1A suppressed pyroptosis in adipocytes by inhibiting the reactive oxygen species/mitogen‐activated protein kinase/caspase‐3 signaling pathway and promoting M2 macrophage polarization. This experiment provides a theoretical basis for understanding the regulatory function and mechanism of PP1A in pyroptosis caused by oxidative stress in adipocytes.

Adipose tissue regulates whole‐body energy homeostasis. Both lipodystrophy and obesity, the extreme and opposite aspects of adipose tissue dysfunction, result in metabolic disorders: insulin resistance and hepatic steatosis. Cyclin‐dependent kinases (CDKs) have been reported to be involved in adipose tissue development and functions. Using adipose tissue‐specific knockout mice, here we demonstrate that the deletion of CDK7 in adipose tissue results in progressive lipodystrophy, insulin resistance, impaired adipokine secretion and downregulation of fat‐specific genes, which are aggravated on high‐fat diet and during ageing. Our studies suggest that CDK7 is a key regulatory component of adipose tissue maintenance and systemic energy homeostasis.