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- Title
12-Lipoxygenase-Null Mice are Resistant to High-Fat-Diet-Induced Metabolic Stress and Islet Dysfunction.
- Authors
Kimble, Sarah D.; Nunemaker, Craig S.; Carter, Jeffrey D.; Chen, Meng; Smith, Kellie M.; Yang, Zandong; Wu, Runpei; Garmey, James C.; Nadler, Jerry L.
- Abstract
Inflammation is considered a key pathological process in dyslipidemia and diabetes mellitus. Activation of 12-lipoxygenase (12-LO), an enzyme involved in fatty acid metabolism; may contribute to inflammatory-mediated beta-cell dysfunction. We investigated whether islets from mice lacking 12-LO were protected from metabolic stress caused by a high fat diet. Age-matched 12-LO-knockout (12-LOKO) mice and wild type C57BL6/J (B6) mice were fed either a standard chow or high fat diet (HFD) for 8 weeks. HFD led to weight gain in both groups, but male B6 mice gained 30-50% more weight than 12-LOKOs in multiple trials (p<0.05). The HFD B6 group showed reduced glucose and insulin tolerance compared to the HFD 12-LOKO and chow-fed groups, suggesting a possible defect in islet function and the peripheral targets of insulin. Proinflammatory circulating adipokines TNF-alpha and IL-6 were increased in HFD B6 mice, whereas adiponectin, the protective adipokine, was decreased. However, HFD 12-LOKO mice remained protected from increases in IL-6 and TNF-alpha or decreases in adiponectin. Histological studies comparing pancreatic tissue revealed that islet area was increased only in HFD B6 mice, a potential indicator of islet compensation to the HFD. Further, caspase-3 staining for apoptosis showed that islets from B6 mice on either diet had increased rates of apoptosis compared to 12-LOKO mice on either diet 036 chow 5.9 ± 1.1; B6 HFD 7.2 ± 1.6; 12-LOKO chow 2.7± 0.6; 12-LOKO HFD 3.3 ± 0.7 nuclei/islet; p<0.05). Isolated islets from HFD B6 mice showed a reduction in glucose-stimulated insulin secretion (5.9 ± 1.18 ng/ml for HFD B6 vs 7.9 ± 1.3, 8.0 ± 0.9, and 7.8 ± 1.6 ng/ml for chow B6, chow 12-LOKO, and HFD 12-LOKO, respectively, p<0.05) and an increase in basal insulin levels (5.0 ± 0.4 ng/ml for HFD B6 vs 3.7 ± 0.7, 3.5 ± 0.9, and 4.1 ± 0.9 ng/ml for chow B6, chow 12-LOKO, and HFD 12-LOKO, respectively, p<0.05), suggesting a loss of glucose sensitivity. Finally, 12-LO activity was increased in HFD B6 mouse islets (HFD: 0.69 ± 0.14 vs. Chow: 0.37 ± 0.08 pmol/mg/min, n=6, p<0.01). These data collectively suggest that 12-LO is a major target for HFD-induced beta-cell toxicity and that reducing 12-LO may prevent metabolic stress and islet dysfunction from hyperlipidemia.
- Subjects
LIPOXYGENASES; ISLANDS of Langerhans; DIETARY fats; PANCREATIC beta cells; METABOLIC disorders; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA441
- ISSN
0012-1797
- Publication type
Article