Targeted Overexpression of Inducible 6-Phosphofructo-2-kinase in Adipose Tissue Increases Fat Deposition but Protects against Diet-induced Insulin Resistance and Inflammatory Responses

Abstract

Background: Inducible 6-phosphofructo-2-kinase links metabolic and inflammatory responses. Results: Adipose overexpression of inducible 6-phosphofructo-2-kinase increases fat deposition, suppresses inflammatory responses, and improves insulin sensitivity in both adipose and liver tissues. Conclusion: Inducible 6-phosphofructo-2-kinase in adipocytes uniquely dissociates diet-induced inflammatory and metabolic responses in both adipose and liver tissues. Significance: Adipocyte-inducible 6-phosphofructo-2-kinase may underlie healthy obesity.

Kinome Screen Identifies PFKFB3 and Glucose Metabolism as Important Regulators of the Insulin/Insulin-like Growth Factor (IGF)-1 Signaling Pathway

“…The rationale for this hierarchical effect of insulin among different tissues is unclear and we speculate this may be related to the unusually high rate of PFKFB3-mediated glycolysis in the fat cell, which potentiates Akt signaling. Consistent with these observations, transgenic mice overexpressing PFKFB3 selectively in adipocytes, exhibit enhanced insulin sensitivity on high fat diet despite increased adiposity (91). Conversely, reduced PFKFB3 in PFKFB3ϩ/Ϫ mice exacerbates diet-induced insulin resistance (52).…”

Type 2 diabetes alters metabolic and transcriptional signatures of glucose and amino acid metabolism during exercise and recovery

“…The glycolytic enzymes HK2 and PFKM and the bidirectional regulators of glycolysis PFKFB1 and PFKFB3 were upregulated after exercise in the diabetic participants. Notably, enhanced expression of PFKFB3 has been shown to be involved in the improvement of insulin sensitivity and protection against inflammation in obese mice [21], indicating a function of PFKFB3 beyond regulation of glycolysis. In addition, we found upregulation of glucose enhancer factor SLC2A4RG, a transcriptional activator of GLUT4 expression [22], in the muscle of diabetic participants after exercise.…”

Myeloid Cell-specific Disruption of Period1 and Period2 Exacerbates Diet-induced Inflammation and Insulin Resistance

“…Myeloid Cell-specific Per1/2 Disruption Exacerbates Liver Inflammatory Responses, Insulin Resistance, and Metabolic Dysregulation-During obesity, adipose tissue inflammation and dysfunction can produce distal effects on liver inflammatory and metabolic responses (43,48), which in turn also contribute to the control of systemic insulin sensitivity and glucose homeostasis. Thus, we used the same BMT-WT and BMT- ldc mice exhibited a significant increase in liver inflammatory responses, indicated by the increases in the phosphorylation of JNK1 (1.7-fold) and NF-B p65 (2-fold) (Fig.…”

“…Adipocytes were differentiated from 3T3-L1 cells in DMEM supplemented with 10 g/ml insulin, 1 M dexamethasone, and 0.5 mM 3-isobutyl-1-methyl-xanthine for 48 h followed by incubation for an additional 6 -8 days in growth medium supplemented with 10 g/ml insulin (7,43). After differentiation, adipocytes were co-cultured with BMDM at a ratio of 10:1 based on the published method (24).…”