Chronic inflammation is a key component of obesity–induced insulin resistance and plays a central role in metabolic disease. In this study, we found that the major insulin target tissues, liver, muscle and adipose tissue exhibit increased levels of the chemotactic eicosanoid LTB4 in obese high fat diet (HFD) mice compared to lean chow fed mice. Inhibition of the LTB4 receptor, Ltb4r1, through either genetic or pharmacologic loss of function results in an anti–inflammatory phenotype with protection from systemic insulin resistance and hepatic steatosis in the setting of both HFD–induced and genetic obesity. Importantly, in vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways in macrophages, promoted de novo hepatic lipogenesis, decreased insulin stimulated glucose uptake in L6 myocytes, increased gluconeogenesis, and impaired insulin–mediated suppression of hepatic glucose output (HGO) in primary mouse hepatocytes. This was accompanied by decreased insulin stimulated Akt phosphorylation and increased Irs1 and Irs2 serine phosphorylation and all of these events were Gαi and Jnk dependent. Taken together, these observations elucidate a novel role of LTB4/Ltb4r1 in the etiology of insulin resistance in hepatocytes and myocytes, and shows that in vivo inhibition of Ltb4r1 leads to robust insulin sensitizing effects.

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Aims/hypothesis Endoplasmic reticulum (ER) stress has been implicated in the development of type 2 diabetes, via effects on obesity, insulin resistance and pancreatic beta cell health. C/EBP homologous protein (CHOP) is induced by ER stress and has a central role in apoptotic execution pathways triggered by ER stress. The aim of this study was to characterise the role of CHOP in obesity and insulin resistance.Methods Metabolic studies were performed in Chop −/− and wild-type C57Bl/6 mice, and included euglycaemichyperinsulinaemic clamps and indirect calorimetry. The inflammatory state of liver and adipose tissue was determined by quantitative RT-PCR, immunohistology and macrophage cultures. Viability and absence of ER stress in islets of Langerhans was determined by electron microscopy, islet culture and quantitative RT-PCR. Results Systemic deletion of Chop induced abdominal obesity and hepatic steatosis. Despite marked obesity, Chop −/− mice had preserved normal glucose tolerance and insulin sensitivity. This discrepancy was accompanied by lower levels of pro-inflammatory cytokines and less infiltration of immune cells into fat and liver. Conclusions/interpretation These observations suggest that insulin resistance is not induced by fat accumulation per se, but rather by the inflammation induced by ectopic fat. CHOP may play a key role in the crosstalk between excessive fat deposition and induction of inflammation-mediated insulin resistance.

Sustained elevated levels of saturated free fatty acids, such as palmitate, contribute to beta cell dysfunction, a phenomenon aggravated by high glucose levels. The aim of this study was to investigate the mechanisms of palmitate-induced beta cell dysfunction and death, combined or not with high glucose. Protein profiling of INS-1E cells, exposed to 0.5 mmol/L palmitate and combined or not with 25 mmol/L glucose, for 24 h was done by 2D-DIGE, both on full cell lysate and on an enriched endoplasmic reticulum (ER) fraction. Eighty-three differentially expressed proteins (P < 0.05) were identified by MALDI-TOF/TOF mass spectrometry and proteomic results were confirmed by functional assays. 2D-DIGE analysis of whole cell lysates and ER enriched samples revealed a high number of proteins compared to previous reports. Palmitate induced beta cell dysfunction and death via ER stress, hampered insulin maturation, generation of harmful metabolites during triglycerides synthesis and altered intracellular trafficking. In combination with high glucose, palmitate induced increased shunting of excess glucose, increased mitochondrial reactive oxygen species production and an elevation in many transcription-related proteins. This study contributes to a better understanding and revealed novel mechanisms of palmitate-induced beta cell dysfunction and death and may provide new targets for drug discovery.

Alpha-synuclein (α-synuclein) is considered a key player in Parkinson's disease (PD), but the exact relationship between α-synuclein aggregation and dopaminergic neurodegeneration remains unresolved. There is increasing evidence that neuroinflammatory processes are closely linked to dopaminergic cell death, but whether the inflammatory process is causally involved in PD or rather reflects secondary consequences of nigrostriatal pathway injury is still under debate. We evaluated the therapeutic effect of the immunophilin ligand FK506 in a rAAV2/7 α-synuclein overexpression rat model. Treatment with FK506 significantly increased the survival of dopaminergic neurons in a dose-dependent manner. No reduction in α-synuclein aggregation was apparent in this time window, but FK506 significantly lowered the infiltration of both T helper and cytotoxic T cells and the number and subtype of microglia and macrophages. These data suggest that the anti-inflammatory properties of FK506 decrease neurodegeneration in this α-synuclein-based PD model, pointing to a causal role of neuroinflammation in the pathogenesis of PD.