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Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet

¹Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; ²Department of Internal Medicine, Touchstone Diabetes Center, University of Texas, Southwestern Medical Center, Dallas, Texas; ³Department of Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan; ⁴Department of Medicine, Harborview Medical Center, University of Washington, ⁵Department of Veterans Affairs Puget Sound Health Care System, ⁶Departments of Medicine and Biological Structure, and ⁷Department of Medicine, University of Washington, Seattle, Washington; ⁸Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio; and ⁹Department of Veterans Affairs Tennessee Valley Healthcare System, and ¹⁰Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University School of Medicine, Nashville, Tennessee

Submitted 18 April 2008 ; accepted in final form 24 December 2008

Weight gain induced by an energy-dense diet is hypothesized to arise in part from defects in the neuronal response to circulating adiposity negative feedback signals, such as insulin. Peripheral tissue insulin resistance involves cellular inflammatory responses thought to be invoked by excess lipid. Therefore, we sought to determine whether similar signaling pathways are activated in the brain of rats fed a high-fat (HF) diet. The ability of intracerebroventricular (icv) insulin to reduce food intake and activate hypothalamic signal transduction is attenuated in HF-fed compared with low-fat (LF)-fed rats. This effect was accompanied by both hypothalamic accumulation of palmitoyl- and stearoyl-CoA and activation of a marker of inflammatory signaling, inhibitor of B kinase-β (IKKβ). Hypothalamic insulin resistance and inflammation were observed with icv palmitate infusion or HF feeding independent of excess caloric intake. Last, we observed that central IKKβ inhibition reduced food intake and was associated with increased hypothalamic insulin sensitivity in rats fed a HF but not a LF diet. These data collectively support a model of diet-induced obesity whereby dietary fat, not excess calories, induces hypothalamic insulin resistance by increasing the content of saturated acyl-CoA species and activating local inflammatory signals, which result in a failure to appropriately regulate food intake.

lipotoxicity; fatty acid; adipose

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