The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity. This has led to a convergence of the fields of immunology and nutrient physiology and the understanding that they are inextricably linked. The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases. In this Review, we highlight the cellular and molecular mechanisms at play in the generation of obesity-induced inflammation. We also emphasize how defining the immune regulation in metabolic tissues has broadened the understanding of the diversity of inflammatory responses.

/pdf/inflammatory-links-between-obesity-and-metabolic-disease-2fxd2fs13s.pdf

Inflammatory links between obesity and metabolic disease.

The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite--sphingosine-1-phosphate (S1P)--independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.

/pdf/receptor-mediated-activation-of-ceramidase-activity-1rgc0mgvct.pdf

Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin

Obesity and type 2 diabetes mellitus are complicated metabolic diseases that affect multiple organs and are characterized by hyperglycaemia. Currently, stable and effective treatments for obesity and type 2 diabetes mellitus are not available. Therefore, the mechanisms leading to obesity and diabetes and more effective ways to treat obesity and diabetes should be identified. Based on accumulated evidences, the PI3K/AKT signalling pathway is required for normal metabolism due to its characteristics, and its imbalance leads to the development of obesity and type 2 diabetes mellitus. This review focuses on the role of PI3K/AKT signalling in the skeletal muscle, adipose tissue, liver, brain and pancreas, and discusses how this signalling pathway affects the development of the aforementioned diseases. We also summarize evidences for recently identified therapeutic targets of the PI3K/AKT pathway as treatments for obesity and type 2 diabetes mellitus. PI3K/AKT pathway damaged in various tissues of the body leads to obesity and type 2 diabetes as the result of insulin resistance, and in turn, insulin resistance exacerbates the PI3K/AKT pathway, forming a vicious circle.

/pdf/the-pi3k-akt-pathway-in-obesity-and-type-2-diabetes-1g2xdzskz0.pdf

The PI3K/AKT pathway in obesity and type 2 diabetes.

Obesity is associated with an enhanced inflammatory response that exacerbates insulin resistance and contributes to diabetes, atherosclerosis, and cardiovascular disease. One mechanism accounting for the increased inflammation associated with obesity is activation of the innate immune signaling pathway triggered by TLR4 recognition of saturated fatty acids, an event that is essential for lipid-induced insulin resistance. Using in vitro and in vivo systems to model lipid induction of TLR4-dependent inflammatory events in rodents, we show here that TLR4 is an upstream signaling component required for saturated fatty acid–induced ceramide biosynthesis. This increase in ceramide production was associated with the upregulation of genes driving ceramide biosynthesis, an event dependent of the activity of the proinflammatory kinase IKKβ. Importantly, increased ceramide production was not required for TLR4-dependent induction of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance. These findings suggest that sphingolipids such as ceramide might be key components of the signaling networks that link lipid-induced inflammatory pathways to the antagonism of insulin action that contributes to diabetes.

/pdf/lipid-induced-insulin-resistance-mediated-by-the-5fwii9vai9.pdf

Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice.

https://www.cell.com/trends/molecular-medicine/pdf/S1471-4914(11)00145-6.pdf

Endoplasmic reticulum stress, obesity and diabetes

Insulin signaling can be modulated by several isoforms of PKC in peripheral tissues. Here, we assessed whether one specific isoform, PKC-θ, was expressed in critical CNS regions that regulate energy balance and whether it mediated the deleterious effects of diets high in fat, specifically palmitic acid, on hypothalamic insulin activity in rats and mice. Using a combination of in situ hybridization and immunohistochemistry, we found that PKC-θ was expressed in discrete neuronal populations of the arcuate nucleus, specifically the neuropeptide Y/agouti-related protein neurons and the dorsal medial nucleus in the hypothalamus. CNS exposure to palmitic acid via direct infusion or by oral gavage increased the localization of PKC-θ to cell membranes in the hypothalamus, which was associated with impaired hypothalamic insulin and leptin signaling. This finding was specific for palmitic acid, as the monounsaturated fatty acid, oleic acid, neither increased membrane localization of PKC-θ nor induced insulin resistance. Finally, arcuate-specific knockdown of PKC-θ attenuated diet-induced obesity and improved insulin signaling. These results suggest that many of the deleterious effects of high-fat diets, specifically those enriched with palmitic acid, are CNS mediated via PKC-θ activation, resulting in reduced insulin activity.

/pdf/palmitic-acid-mediates-hypothalamic-insulin-resistance-by-z225nq4soo.pdf

Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents

/pdf/palmitic-acid-mediates-hypothalamic-insulin-resistance-by-1fbhamda82.pdf

Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents (Journal of Clinical Investigation (2010) 120, 1 (394) DOI: 10.1172/JCI36714C1)

Original citation: J. Clin. Invest. 2010;120(1):394. doi:10.1172/JCI36714C1. Citation for this corrigendum: J. Clin. Invest. 2011;121(1):456. doi:10.1172/JCI45846. In the Methods section titled “Fatty acid infusion,” the dose of fatty acids delivered centrally was given incorrectly. The correct sentence appears below. The cannula was connected via a polyethylene catheter to a subcutaneous osmotic minipump (Alza Corporation) filled with either palmitic or oleic acid (equimolar concentrations, 50 μmol/l; Sigma-Aldrich) or vehicle (PBS) for continuous infusion over 3 days. The authors regret the error. Corrigendum

/pdf/palmitic-acid-mediates-hypothalamic-insulin-resistance-by-bzj0vx6uoy.pdf

Palmitic acid mediates hypothalamic insulin resistance by altering PKC-q subcellular localization in rodents (Journal of Clinical Investigation (2009) 119, (2577-2589))

Anne Laure Lefevre

Papers

Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents

Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents (Journal of Clinical Investigation (2010) 120, 1 (394) DOI: 10.1172/JCI36714C1)

Palmitic acid mediates hypothalamic insulin resistance by altering PKC-q subcellular localization in rodents (Journal of Clinical Investigation (2009) 119, (2577-2589))