Mechanisms of LXR-mediated control of obesity-induced metaflammation and insulin-resistance

Abstract

Obesity is nowadays considered a pandemic disease, and its incidence correlates with the concomitant increase of a set of associated comorbidities, including T2D, cardiovascular diseases, fatty liver disease, among others, which are all grouped within the metabolic syndrome. Insulin resistance is frequently developed in obesity and seems to be a common link to these associated diseases. Many efforts have focused in deciphering the mechanisms underlying insulin resistance, being metaflammation, that is the chronic low grade inflammatory response in the adipose tissue associated to obesity, the most well-documented. In this scenario, it is urgent to explore the relevance of anti-inflammatory actors as insulin-sensitizing agents.

The nuclear receptors LXRs represent interesting therapeutic targets that can be pharmacologically activated by synthetic high affinity agonists. Accumulated evidence, including work from our group, indicates the importance of the LXR pathway in the negative control of inflammatory conditions. In this work we have focused in better understanding several aspects of LXR biology. On one side, using primary murine macrophages, our results suggest that negative crosstalk between LXRs and the pro- inflammatory transcription factor IRF1 occurs in a gene-specific manner during the macrophage response to IFN-!. Notably, IRF1 plays a fine-tuning role in the control of the expression of the LXR target CD38. On the other side, we have evaluated the consequences of LXR activation in a murine model of obesity-associated insulin resistance. Pharmacological administration of an LXR agonist resulted in decreased body weight and basal glycemia and in improved systemic insulin sensitivity in diet-induced obese mice. However, these effects did not correlate with broad inhibitory actions on metaflammation. Our results suggest that the insulin-sensitizing actions mediated by LXRs require functional systemic expression of the multi-functional protein CD38, but these effects do not depend on CD38 expression specifically in bone marrow-derived cells. In addition, our studies indicate that CD38-deficient mice are partially protected from both the increase in adiposity and the development of insulin resistance in response to a high fat diet, and this phenotype is not mediated by the lack of expression of CD38 in bone marrow-derived cells.

In summary, this work unravels the importance of the multi-enzymatic protein CD38 in the insulin- sensitizing actions of the LXR pathway and opens the door to more precisely characterize the function of the LXR-CD38 axis specifically in metabolic cell compartments.