Cytokines in the Progression of Pancreatic β-Cell Dysfunction

The dysfunction of pancreatic β-cell and the reduction in β-cell mass are the decisive events in the progression of type 2 diabetes. There is increasing evidence that cytokines play important roles in the procedure of β-cell failure. Cytokines, such as IL-1β, IFN-γ, TNF-α, leptin, resistin, adiponectin, and visfatin, have been shown to diversely regulate pancreatic β-cell function. Recently, islet-derived cytokine PANcreatic DERived factor (PANDER or FAM3B) has also been demonstrated to be a regulator of islet β-cell function. The change in cytokine profile in islet and plasma is associated with pancreatic β-cell dysfunction and apoptosis. In this paper, we summarize and discuss the recent studies on the effects of certain important cytokines on pancreatic β-cell function. The imbalance in deleterious and protective cytokines plays pivotal roles in the development and progression of pancreatic β-cell dysfunction under insulin-resistant conditions

Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice

Inflammatory factors secreted by macrophages play an important role in obesity-related insulin resistance. Being at the crossroads of a nutrient-hormonal signalling network, the mammalian target of rapamycin complex 1 (mTORC1) controls important functions in the regulation of energy balance and peripheral metabolism. However, the role of macrophage mTORC1 in insulin resistance is still unclear. In the current study, we investigated the physiological role of macrophage mTORC1 in regulating inflammation and insulin sensitivity. We generated mice deficient in the regulatory associated protein of mTOR (Raptor) in macrophages, by crossing Raptor (also known as Rptor) floxed mice (Raptor (flox/flox)) with mice expressing Cre recombinase under the control of the Lysm-Cre promoter (Mac-Raptor (KO)). We fed mice chow or high-fat diet (HFD) and assessed insulin sensitivity in liver, muscle and adipose tissue. Subsequently, we measured inflammatory gene expression in liver and adipose tissue and investigated the role of Raptor deficiency in the regulation of inflammatory responses in peritoneal macrophages from HFD-fed mice or in palmitic acid-stimulated bone marrow-derived macrophages (BMDMs). Mac-Raptor (KO) mice fed HFD had improved systemic insulin sensitivity compared with Raptor (flox/flox) mice. Macrophage Raptor deficiency reduced inflammatory gene expression in liver and adipose tissue, fatty liver and adipose tissue macrophage content in response to HFD. In peritoneal macrophages from mice fed with an HFD for 12 weeks, macrophage Raptor deficiency decreased inflammatory gene expression, through attenuation of the inactivation of Akt and subsequent inhibition of the inositol-requiring element 1α/clun NH2-terminal kinase-nuclear factor kappa-light-chain-enhancer of activated B cells (IRE1α/JNK/NFκB) pathways. Similarly, mTOR inhibition as a result of Raptor deficiency or rapamycin treatment decreased palmitic acid-induced inflammatory gene expression in BMDMs in vitro. The disruption of mTORC1 signalling in macrophages protects mice against inflammation and insulin resistance potentially by inhibiting HFD- and palmitic acid-induced IRE1α/JNK/NFκB pathway activatio

Mtorc1 Pathway Disruption Ameliorates Brain Inflammation Following Stroke Via A Shift In Microglia Phenotype From M1 Type To M2 Type

Inflammatory factors secreted by microglia play an important role in focal ischemic stroke. The mammalian target of rapamycin (mTOR) pathway is a known regulator of immune responses, but the role thatmTORC1 signaling plays in poststroke neuroinflammation is not clear. To explore the relationship betweenmicroglial action in the mTORC1 pathway and the impact on stroke, we administered the mTORC1 inhibitors sirolimus and everolimus to mice. Presumably, disrupting the mTORC1 pathway after focal ischemic stroke should clarify the subsequent activity ofmicroglia. For that purpose,we generated mice deficient in the regulatory associated protein ofmTOR(Raptor) inmicroglia,whosemTORC1signalingwas blocked, by crossing Raptor loxed (Raptorflox/flox)mice with CX3CR1CreER mice, which express Cre recombinase under the control of the CX3C chemokine receptor 1 promoter. mTORC1 blockade reduced lesion size, improved motor function, dramatically decreased production of proinflammatory cytokines and chemokines, and reduced the number ofM1 type microglia. Thus, mTORC1 blockade apparently attenuated behavioral deficits and poststroke inflammation after middle cerebral artery occlusion by preventingmicroglia polarization toward theM1 type.-Li, D.,Wang, C., Yao, Y., Chen, L., Liu, G.,Zhang, R., Liu,Q., Shi, F.-D., Hao, J. mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype fromM1 type toM2 type

Macrophage Raptor Deficiency-Induced Lysosome Dysfunction Exacerbates Nonalcoholic SteatohepatitisSummary

Background & Aims: Nonalcoholic steatohepatitis (NASH) is an increasingly prevalent nonalcoholic fatty liver disease, characterized by inflammatory cell infiltration and hepatocellular damage. Mammalian target of rapamycin complex 1 (mTORC1) has been investigated extensively in the context of cancer, including hepatocellular carcinoma. However, the role of mTORC1 in NASH remains largely unknown. Methods: mTORC1 activity in macrophages in human mild and severe NASH liver was compared. Mice with macrophage-specific deletion of the regulatory-associated protein of mTOR (Raptor) subunit and littermate controls were fed a high-fructose, palmitate, and cholesterol diet for 24 weeks or a methionine- and choline-deficient diet for 4 weeks to develop NASH. Results: We report that in human beings bearing NASH, macrophage mTORC1 activity was lower in livers experiencing severe vs mild NASH liver. Moreover, macrophage mTORC1 disruption exacerbated the inflammatory response in 2 diet-induced NASH mouse models. Mechanistically, in response to apoptotic hepatocytes (AHs), macrophage polarization toward a M2 anti-inflammatory phenotype was inhibited in Raptor-deficient macrophages. During the digestion of AHs, macrophage mTORC1 was activated and coupled with dynamin-related protein 1 to facilitate the latter’s phosphorylation, leading to mitochondrial fission-mediated calcium release. Ionomycin or A23187, calcium ionophores, prevented Raptor deficiency–mediated failure of lysosome acidification and subsequent lipolysis. Blocking dynamin-related protein 1–dependent mitochondria fission impaired lysosome function, resulting in reduced production of anti-inflammatory factors such as interleukins 10 and 13. Conclusions: Persistent mTORC1 deficiency in macrophages contributes to the progression of NASH by causing lysosome dysfunction and subsequently attenuating anti-inflammatory M2-like response in macrophages during clearance of AHs. Keywords: mTORC1, NASH, Lysosome, Drp

Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity

The dataset contains the source data of the study "Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity