Mechanisms mediating insulin resistance in transgenic mice overexpressing mouse apolipoprotein A-II

Abstract

We previously demonstrated that transgenic mice overexpressing mouse apolipoprotein A-II (apoA-II) exhibit several traits associated with the insulin resistance (IR) syndrome, including increased atherosclerosis, hypertriglyceridemia, obesity, and IR. The skeletal muscle appeared to be the insulin-resistant tissue in the apoA-II transgenic mice. We now demonstrate a decrease in FA oxidation in skeletal muscle of apoA-II transgenic mice, consistent with reports that decreased skeletal muscle FA oxidation is associated with increased skeletal muscle triglyceride accumulation, skeletal muscle IR, and obesity. The decrease in FA oxidation is not due to decreased carnitine palmitoyltransferase 1 activity, because oxidation of palmitate and octanoate were similarly decreased. Alterations in both glucose and lipid metabolism are two consistent features of the insulin resistance (IR) syndrome) (1, 2). Several studies have demonstrated that primary changes in FA metabolism can lead to IR (3-8). Although much has been learned about the insulin signaling pathways and the metabolism of both glucose and FAs, the underlying cause of most cases of IRS and type 2 diabetes is unknown (9, 10). Whether primary defects in FA metabolism or glucose metabolism underlie the majority of human cases of IRS and type 2 diabetes remains to be determined.Studies using genetically altered mice have demonstrated that both the scavenger receptor CD36 and the HDL-associated protein apolipoprotein A-II (apoA-II) alter FA metabolism and IR (11-16). Furthermore, HDL is a ligand for the CD36 receptor, which raises the possibility of an HDL-CD36 interaction that affects FA metabolism (15). Mice with a null mutation for apoA-II exhibit increased sensitivity to insulin, with decreased plasma concentrations of triglycerides, FFA, and glucose (11). We previously demonstrated that increasing plasma concentrations of mouse apoA-II in transgenic mice produced several aspects of the IR syndrome including hypertriglyceridemia, obesity, and IR, as well as increased atherosclerotic lesion development (12,(17)(18)(19). The skeletal muscle appeared to be the insulin-resistant tissue in the apoA-II transgenic mice, whereas the liver and adipose tissue in the apoA-II trangenic mice appeared to respond normally (12). Compared with control mice, isolated soleus muscles from the apoA-II transgenic mice exhibited decreased glucose uptake and increased triglyceride accumulation (12). We hypothesize that primary alterations in FA metabolism in skeletal muscle initiate IR and promote the development of obesity. In the present study, we demonstrate that FA oxidation is reduced in the skeletal muscle of apoA-II transgenic mice, which could initiate the metabolic events that lead to skeletal muscle IR. We also placed the apoA-II transgene onto a CD36 knockout background and demonstrated that plasma triglyceride and insulin concentrations are not markedly different in the apoA-II transgenic mice, whether or Abbreviations: apoA-II, apolipoprotein A-II; CPT-1, carnitin...

Apolipoprotein AII Is a Regulator of Very Low Density Lipoprotein Metabolism and Insulin Resistance

“…Treatment of the apoAIItg mice with an insulinsensitizing PPAR␥ agonist ameliorated the insulin resistance and hypertriglyceridemia (20). This suggested that the hypertriglyceridemia was mostly a consequence of the insulin resistance, consistent with the hypothesis described above.…”

“…Additional evidence for other physiologic effects of apoAII has come from genetic studies in both humans and mice, which suggest a role for apoAII in triglyceride and free fatty acid metabolism (8 -10). Subsequently, studies of genetically modified mice carrying a transgene for either human or mouse apoAII (3,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), as well as apoAII knockout mice (22), confirmed a complex metabolic role for apoAII, including a rather profound effect on plasma triglyceride concentrations.…”

“…We previously demonstrated that mice, which overexpress mouse apoA-II, exhibit a marked hypertriglyceridemia, hypercholesterolemia, and increased plasma FFA, as well as insulin resistance, increased adiposity, and increased atherosclerosis (3,5,6,20,21). Treatment of the apoAIItg mice with an insulinsensitizing PPAR␥ agonist ameliorated the insulin resistance and hypertriglyceridemia (20).…”

Transgenic mice express human MPO −463G/A alleles at atherosclerotic lesions, developing hyperlipidemia and obesity in −463G males

“…Total cholesterol, HDL, triglycerides, and free fatty acid concentrations were determined as described previously (26). HDL-cholesterol was quantitated after precipitation of VLDL and LDL with heparin and manganese chloride.…”

Expression of scleraxis and tenascin C in equine adipose and umbilical cord blood derived stem cells is dependent upon substrata and FGF supplementation

“…The resulting cDNA was amplified with SYBR Green PCR Master Mix (Applied Biosystems, Foster City, CA, USA) and the appropriate forward and reverse primers (Table 1; 20 pM) in an ABI 7300 Real-Time PCR System (Applied Biosystems). Thermal cycling parameters included a denature step of 95°C for 10 min and (Castellani et al 2004). Fold change was calculated using the DDCt method.…”