Enhancing liver mitochondrial fatty acid oxidation capacity in obese mice improves insulin sensitivity independently of hepatic steatosis

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

“…This distal dissociation is consistent with liver phenotypes reported in mice in which the liver selectively overexpresses human diacylglycerol acyltransferase (15) and in mice that are treated with adenovirus to overexpress mCPT1a (16). However, unlike the two studies in which the liver originates metabolic alternations (15,16), the aP2-PFKFB3 approach of this study suggests that adipose tissue initiated a dissociation of fat deposition and the inflammatory response, and the liver responded in a similar pattern. As substantial evidence, treatment of mouse primary hepatocytes with conditioned medium of PFKFB3/iPFK2-overexpressing adipocytes recapitulated liver phenotypes observed in HFD-fed Tg mice.…”

“…Although it is commonly accepted that a vicious cycle exists within fat deposition, the inflammatory response, and insulin resistance, increasing evidence also indicates that these metabolic and inflammatory events can be dissociated (13)(14)(15)(16)35). As additional evidence, global disruption of PFKFB3/iPFK2 blunts diet-induced adiposity but exacerbates adipose tissue inflammatory response and systemic insulin resistance (20).…”

“…Overexpression of PFKFB3/iPFK2 in Adipose Tissue Alters Tissue and Plasma Lipid Profiles-Given that PFKFB3/iPFK2 overexpression in adipose tissue promotes fat deposition and that fat composition but not fat content determines tissue proinflammatory status and insulin sensitivity (16,32), the lipid profiles in both adipose and liver tissues were analyzed. Compared with controls, the levels of palmitoleate, a putative antiinflammatory unsaturated fatty acid (32), were increased in both TG and FFA isolated from HFD-fed Tg mouse adipose tissue (Fig.…”

“…Upon targeted overexpressing human acyl-CoA:diacylglycerol acyltransferase in the liver, the transgenic mice exhibit an increase in hepatic steatosis, yet display normal glucose tolerance and systemic insulin sensitivity and normal liver inflammatory response (15). When malonyl-CoA-insensitive CPT1a (mCPT1a) is overexpressed in the liver in both dietinduced and genetically obese mice, the liver inflammatory response decreases independently of hepatic steatosis (16). Precisely how fat deposition alters inflammatory responses and insulin signaling in both adipose and liver tissues in opposite ways is not fully understood, but it may be attributable to the composition of fat deposited rather than the amount of fat deposition (16).…”

“…When malonyl-CoA-insensitive CPT1a (mCPT1a) is overexpressed in the liver in both dietinduced and genetically obese mice, the liver inflammatory response decreases independently of hepatic steatosis (16). Precisely how fat deposition alters inflammatory responses and insulin signaling in both adipose and liver tissues in opposite ways is not fully understood, but it may be attributable to the composition of fat deposited rather than the amount of fat deposition (16).…”