Turner, N and Kowalski, GM and Leslie, SJ and Risis, S and Yang, C and Lee-Young, RS and Babb, JR and Meikle, PJ and Lancaster, GI and Henstridge, DC and White, PJ and Kraegen, EW and Marette, A and Cooney, GJ and Febbraio, MA and Bruce, CR, Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding, Diabetologia, 56, (7) pp. 1638-1648. ISSN 0012-186X (2013) [Refereed Article]
Copyright 2013 Springer-Verlag Berlin Heidelberg
Aims/hypothesis: While it is well known that diet-induced obesity causes insulin resistance, the precise mechanisms underpinning the initiation of insulin resistance are unclear. To determine factors that may cause insulin resistance, we have performed a detailed time-course study in mice fed a high-fat diet (HFD).
Methods: C57Bl/6 mice were fed chow or an HFD from 3 days to 16 weeks and glucose tolerance and tissue-specific insulin action were determined. Tissue lipid profiles were analysed by mass spectrometry and inflammatory markers were measured in adipose tissue, liver and skeletal muscle.
Results: Glucose intolerance developed within 3 days of the HFD and did not deteriorate further in the period to 12 weeks. Whole-body insulin resistance, measured by hyperinsulinaemic-euglycaemic clamp, was detected after 1 week of HFD and was due to hepatic insulin resistance. Adipose tissue was insulin resistant after 1 week, while skeletal muscle displayed insulin resistance at 3 weeks, coinciding with a defect in glucose disposal. Interestingly, no further deterioration in insulin sensitivity was observed in any tissue after this initial defect. Diacylglycerol content was increased in liver and muscle when insulin resistance first developed, while the onset of insulin resistance in adipose tissue was associated with increases in ceramide and sphingomyelin. Adipose tissue inflammation was only detected at 16 weeks of HFD and did not correlate with the induction of insulin resistance.
Conclusions/interpretation: HFD-induced whole-body insulin resistance is initiated by impaired hepatic insulin action and exacerbated by skeletal muscle insulin resistance and is associated with the accumulation of specific bioactive lipid species.
|Item Type:||Refereed Article|
|Keywords:||euglycaemic-hyperinsulinaemic clamp, high-fat diet, insulin resistance, lipotoxicity, ceramide, diacylglycerol, glucose, insulin, lipid, sphingomyelin, adipose tissue, animal experiment, animal food, animal tissue, article, controlled study, male|
|Research Division:||Biological Sciences|
|Research Group:||Biochemistry and cell biology|
|Research Field:||Cell metabolism|
|Objective Group:||Clinical health|
|Objective Field:||Clinical health not elsewhere classified|
|UTAS Author:||Henstridge, DC (Mr Darren Henstridge)|
|Web of Science® Times Cited:||248|
|Deposited By:||Health Sciences|
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