Insulin resistance is the pivotal pathogenic component of many metabolic diseases, including type 2 diabetes mellitus, and is defined as a state of reduced responsiveness of insulin-targeting tissues to physiological levels of insulin. Although the underlying mechanism of insulin resistance is not fully understood, several credible theories have been proposed. In this review, we summarize the functions of insulin in glucose metabolism in typical metabolic tissues and describe the mechanisms proposed to underlie insulin resistance, that is, ectopic lipid accumulation in liver and skeletal muscle, endoplasmic reticulum stress, and inflammation. In addition, we suggest potential therapeutic strategies for addressing insulin resistance.

Accumulating data have indicated a fundamental role of eosinophils in regulating adipose tissue homeostasis. Here, we performed whole-genome RNA sequencing of the small intestinal tract, which suggested the presence of impaired lipid metabolism in eosinophil-deficient ΔdblGATA mice. ΔdblGATA mice fed a high-fat diet (HFD) showed reduced body fat mass, impaired enlargement of adipocytes, decreased expression of adipogenic genes, and developed glucose intolerance. HFD induced accumulation of eosinophils in the perigonadal white adipose tissue. Concordantly, adipocyte-differentiated 3T3-L1 cells promoted the migration of eosinophils through the expression of CCL11 (eotaxin-1) and likely promoted their survival through the expression of interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor. HFD-fed ΔdblGATA mice showed increased infiltration of macrophages, CD4+ T-cells, and B-cells, increased expression of interferon-γ, and decreased expression of IL-4 and IL-13 in white adipose tissue. Interferon-γ treatment significantly decreased lipid deposition in adipocyte-differentiated 3T3-L1 cells, while IL-4 treatment promoted lipid accumulation. Notably, HFD-fed ΔdblGATA mice showed increased lipid storage in the liver as compared with wild-type mice. We propose that obesity promotes the infiltration of eosinophils into adipose tissue that subsequently contribute to the metabolic homeostasis by promoting adipocyte maturation.

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Adipose tissues considerably influence metabolic homeostasis, and both white (WAT) and brown (BAT) adipose tissue play significant roles in lipid and glucose metabolism. -linked-acetylglucosamine (-GlcNAc) modification is characterized by the addition of -acetylglucosamine to various proteins by-GlcNAc transferase (Ogt), subsequently modulating various cellular processes. However, little is known about the role of -GlcNAc modification in adipose tissues. Here, we report the critical role of-GlcNAc modification in cold-induced thermogenesis. Deletion of in WAT and BAT using adiponectin promoter-driven Cre recombinase resulted in severe cold intolerance with decreased uncoupling protein 1 (Ucp1) expression. Furthermore, deletion led to decreased mitochondrial protein expression in conjunction with decreased peroxisome proliferator-activated receptor γ coactivator 1-α protein expression. This phenotype was further confirmed by deletion of in BAT using Ucp1 promoter-driven Cre recombinase, suggesting that-GlcNAc modification in BAT is responsible for cold-induced thermogenesis. Hypothermia was significant under fasting conditions. This effect was mitigated after normal diet consumption but not after consumption of a fatty acid-rich ketogenic diet lacking carbohydrates, suggesting impaired diet-induced thermogenesis, particularly by fat. In conclusion, -GlcNAc modification is essential for cold-induced thermogenesis and mitochondrial biogenesis in BAT. Glucose flux into BAT may be a signal to maintain BAT physiological responses.