In vivo multi‐tissue efficacy of peroxisome proliferator‐activated receptor‐γ therapy on glucose and fatty acid metabolism in obese type 2 diabetic rats

Abstract

ObjectiveTo identify the disturbances in glucose and lipid metabolism observed in Type 2 Diabetes Mellitus (T2DM), we examined the interaction and contribution of multiple tissues (liver, heart, muscle, and brown adipose tissue) and monitored the effects of the PPARγ agonist rosiglitazone (RGZ) on metabolism in these tissues.Design and MethodsRates of [18F]FDG and [11C]Palmitate uptake and utilization in the Zucker Diabetic Fatty (ZDF) rat were quantified using non-invasive positron emission tomography (PET) imaging and quantitative modeling in comparison to lean Zucker rats. Furthermore, we studied two separate groups of RGZ-treated and untreated ZDF ratsResultsGlucose uptake is impaired in ZDF brown fat, muscle, and heart tissues compared to leans, while RGZ treatment increased glucose uptake compared to untreated ZDF rats. Fatty acid (FA) uptake decreased, but FA flux increased in brown fat and skeletal muscle of ZDF rats. RGZ treatment increased uptake of FA in brown fat, but decreased uptake and utilization in liver, muscle and heart.ConclusionOur data indicate tissue-specific mechanisms for glucose and FA disposal as well a differential action of insulin-sensitizing drugs to normalize substrate handling and highlight the role that pre-clinical imaging may play in screening drugs for obesity and diabetes.

High‐fat diet‐induced changes in liver thioredoxin and thioredoxin reductase as a novel feature of insulin resistance

“…A variety of proteins have been described to participate in lipid metabolism. For instance, activation of peroxisome proliferator-activated receptor (PPAR)γ can increase uptake of fatty acid in brown fat, but decrease uptake and utilization of fatty acid in liver [22] ; PPARα activation favors fatty acid oxidation in liver [23] ; leptin negatively regulates PPARγ gene expression [24] ; inhibition of protein tyrosine phosphatase-1B (PTP-1B) reduces TG accumulation in addition to improving insulin sensitivity [25] . Using ELISA, we observed that HFD group had a significant decrease in hepatic PPARγ ( Fig.…”

Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer

“…Nevertheless, many prior reports have linked obesity and insulin resistance with increased myocardial fatty acid uptake and utilization (6, 8, 10, 13, 26, 37, 38, 48, 49, 56 -58, 62). Furthermore, it is apparent from a number of experimental studies limiting or augmenting fatty acid uptake that the increased fatty acid uptake can contribute to impairments in myocardial function (2,22,25,28,34,44,48,50,51,59,73).…”

Rosiglitazone, a PPARγ agonist, ameliorates palmitate‐induced insulin resistance and apoptosis in skeletal muscle cells

“…Thiazolidindiones (TZDs), the peroxisome proliferator‐activated receptor γ (PPAR γ ) agonists, are the first insulin‐sensitive drugs that have been used to treat type 2 diabetes. Many findings support the idea that TZDs can correct the abnormalities of glucose metabolism in skeletal muscle in vivo . It has been reported that rosiglitazone (RSG), the PPAR γ agonist, ameliorates skeletal muscle insulin resistance by reducing the fat flux from adipose tissue to skeletal muscle .…”

“…Many findings support the idea that TZDs can correct the abnormalities of glucose metabolism in skeletal muscle in vivo. [16][17][18] It has been reported that rosiglitazone (RSG), the PPARγ agonist, ameliorates skeletal muscle insulin resistance by reducing the fat flux from adipose tissue to skeletal muscle. 19 In addition to insulin resistance, apoptosis is also affected by TZDs in a cell-specific manner.…”