Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet.
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 kappaB kinase-beta (IKKbeta). Hypothalamic insulin resistance and inflammation were observed with icv palmitate infusion or HF feeding independent of excess caloric intake. Last, we observed that central IKKbeta 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.
Posey
Kelly A
KA
Vanderbilt Medical Center, Nashville TN 37232, USA.
Clegg
Deborah J
DJ
Printz
Richard L
RL
Byun
Jaeman
J
Morton
Gregory J
GJ
Vivekanandan-Giri
Anuradha
A
Pennathur
Subramaniam
S
Baskin
Denis G
DG
Heinecke
Jay W
JW
Woods
Stephen C
SC
Schwartz
Michael W
MW
Niswender
Kevin D
KD
D000818:Animals; D001835:Body Weight; D004041:Dietary Fats / Q000008:administration & dosage* / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D018565:Food-Drug Interactions; D005951:Glucose Tolerance Test; D007033:Hypothalamus, Middle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051550:I-kappa B Kinase / Q000378:metabolism; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects; D009765:Obesity / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020318:Rats, Long-Evans; D012528:Satiety Response / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D004041:Dietary Fats; D007328:Insulin; D020738:Leptin; D051550:I-kappa B Kinase