Distinct gene signatures predict insulin resistance in young mice with high fat diet-induced obesity.

Highly inbred C57BL/6 mice show wide variation in their degree of insulin resistance in response to diet-induced obesity even though they are almost genetically identical. Here we employed transcriptional profiling by RNA sequencing (RNA-Seq) of visceral adipose tissue (VAT) and liver in young mice to determine how gene expression patterns correlate with the later development of high-fat diet (HFD)-induced insulin resistance in adulthood. To accomplish this goal, we partially removed and banked tissues from pubertal mice. Mice subsequently received HFD followed by metabolic phenotyping to identify two well-defined groups of mice with either severe or mild insulin resistance. The remaining tissues were collected at study termination. We then applied RNA-Seq to generate transcriptome profiles associated with worsened insulin resistance before and after the initiation of HFD. We found 244 up- and 109 downregulated genes in VAT of the most insulin-resistant mice even before HFD exposure. Downregulated genes included serine protease inhibitor, major urinary protein, and complement genes; upregulated genes represented mostly muscle constituents. These gene families were also differentially expressed in VAT of mice with high or low insulin resistance after HFD. Inflammatory genes predicted insulin resistance in liver, but not in VAT. In contrast, when we compared VAT of all mice before and after HFD, differentially expressed genes were predominantly composed of immune response genes. These data show a distinct set of gene transcripts in young mice correlates with the severity of insulin resistance in adulthood, providing insight into the pathogenesis of insulin resistance in early life.

Dual actions of a novel bifunctional compound to lower glucose in mice with diet-induced insulin resistance.

Docosahexaenoic acid (DHA 22:6n-3) and salicylate are both known to exert anti-inflammatory effects. This study investigated the effects of a novel bifunctional drug compound consisting of DHA and salicylate linked together by a small molecule that is stable in plasma but hydrolyzed in the cytoplasm. The components of the bifunctional compound acted synergistically to reduce inflammation mediated via nuclear factor κB in cultured macrophages. Notably, oral administration of the bifunctional compound acted in two distinct ways to mitigate hyperglycemia in high-fat diet-induced insulin resistance. In mice with diet-induced obesity, the compound lowered blood glucose by reducing hepatic insulin resistance. It also had an immediate glucose-lowering effect that was secondary to enhanced glucagon-like peptide-1 (GLP-1) secretion and abrogated by the administration of exendin(9-39), a GLP-1 receptor antagonist. These results suggest that the bifunctional compound could be an effective treatment for individuals with type 2 diabetes and insulin resistance. This strategy could also be employed in other disease conditions characterized by chronic inflammation.