IKKε Is Key to Induction of Insulin Resistance in the Hypothalamus, and Its Inhibition Reverses Obesity

May 10, 2014Diabetes

The role of IKKε in causing insulin resistance in the brain’s appetite control area and how blocking it can reverse obesity

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

IKKε knockout mice on a high-fat diet were protected from insulin resistance.

IKKε is expressed in neurons and is increased in the hypothalamus of obese mice.
Blocking IKKε in the hypothalamus reduced inflammation and decreased NF-κB activation.
Inhibition of IKKε improved insulin and leptin signaling pathways without affecting body weight or food intake.
Enhanced insulin action in the hypothalamus may lead to decreased fat accumulation and increased energy expenditure.
Improvement in insulin action correlated with reduced glucose production in the liver of high-fat diet-fed and db/db mice.

AI simplified

IKK epsilon (IKKε) is induced by the activation of nuclear factor-κB (NF-κB). Whole-body IKKε knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKKε is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKKε in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-κB activation in this tissue, relieving the inflammatory environment. Inhibition of IKKε activity, but not TBK1, reduced IRS-1(Ser307) phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. We suggest that IKKε may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism.

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text ↗

IKKε Is Key to Induction of Insulin Resistance in the Hypothalamus, and Its Inhibition Reverses Obesity

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief