Disruption of Inducible 6-Phosphofructo-2-kinase Ameliorates Diet-induced Adiposity but Exacerbates Systemic Insulin Resistance and Adipose Tissue Inflammatory Response

Abstract

Adiposity is commonly associated with adipose tissue dysfunction and many overnutrition-related metabolic diseases including type 2 diabetes. Much attention has been paid to reducing adiposity as a way to improve adipose tissue function and systemic insulin sensitivity. PFKFB3/iPFK2 is a master regulator of adipocyte nutrient metabolism. Using PFKFB3 In an in vitro system, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes caused a decrease in the rate of glucose incorporation into lipid but an increase in the production of reactive oxygen species. Furthermore, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes inappropriately altered the expression of adipokines, decreased insulin signaling, increased the phosphorylation states of JNK and NFB p65, and enhanced the production of proinflammatory cytokines. Together, these data suggest that PFKFB3/iPFK2, although contributing to adiposity, protects against diet-induced insulin resistance and adipose tissue inflammatory response.

Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers

“…Then, the electrons produced flow to Coenzyme Q, which has been shown by microarray to be downregulated in our obese-susceptible subjects. It can be speculated that this observation could explain the downregulation of transcripts encoding for enzymes of glycolyis pathway such as PFKFB3, which is highly expressed in adipose tissue and seems to exert a function that contributes to adiposity, but, on the other hand, protects against the inflammatory response of adipose tissue and the insulin resistance induced by diet (16). Thus, the downregulation in gene transcripts involved in the glycolytic pathway in obese subjects is in agreement with and could explain the lower postpandrial carbohydrate oxidation that we observed in these obese-susceptible subjects (25).…”

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

“…All mice were maintained on a 12:12-h light/dark cycle (lights on at 06:00). At 5-6 weeks of age, male mice were fed an HFD (60% fat calories, 20% protein calories, and 20 carbohydrate calories) or a low fat diet (LFD) (10% fat calories, 20% protein calories, and 70 carbohydrate calories) for 12 weeks as described previously (20,21). After the feeding regimen, mice were fasted for 4 h before sacrifice for collection of blood and tissue samples (24 -26).…”

“…For insulin tolerance tests, blood samples (5 l) were collected from the tail vein before and at 15,30,45, and 60 min after the bolus insulin injection. Similarly, for glucose tolerance tests, blood samples were collected from the tail vein before and at 30, 60, 90, and 120 min after the glucose bolus injection (20,21).…”

“…The amount of iPFK2 in white adipose tissue, liver, muscle, and bone marrow samples was determined using Western blot analyses (20,21).…”

“…Recent evidence demonstrates that global disruption of PFKFB3/iPFK2 blunts diet-induced adiposity but exacerbates adipose tissue inflammatory response and systemic insulin resistance (20). Additionally, PFKFB3/iPFK2 is involved in the anti-inflammatory and anti-diabetic effects of PPAR␥ activation likely by promoting fat synthesis in adipose tissue (21).…”