Role of IKK-beta/NF-kappaB in hypothalamic dysregulation of energy balance

Project: Research project

Project Details

Description

Body weight and energy balance are maintained by neurons in the hypothalamus. Insulin signaling in
hypothalamic neurons plays a pivotal role in preventing excessive energy accumulation and obesity, since
mpairment or loss of hypothalamic insulin signaling is sufficient to cause energy imbalance leading to
obesity and type 2 diabetes (T2D). Recent advances show that persistent nutrient overload induces
hypothalamic insensitivity to insulin; however, the molecular basis for this is unclear. Following our previous
discovery that pro-inflammatory nuclear transcription factor NF-KB and its upstream activator IKKp are
activated in peripheral tissues by a high-fat diet to induce local insulin resistance, this proposal will
nvestigate the role of IKKp/NF-KB in hypothalamic dysregulation of insulin signaling and energy balance.
Preliminary results show that high-fat diet activates IKKp/NF-KB in mouse hypothalamus, and activation of
KKp/NF-KB impairs hypothalamic insulin action both in vitro and in vivo. Animal tests further show that the
selective activation of IKKp/NF-KB in mediobasal hypothalamus induced weight gain, while the suppression
of this pathway in insulin-sensitizing hypothalamic neurons protected against dietary obesity. Based on these
research contexts and preliminary data, this proposal hypothesizes that chronic challenges of nutritional
excess activate IKKp/NF-KB in the hypothalamus, desensitize hypothalamic neurons to insulin, and cause
energy imbalance leading to obesity and T2D. This hypothesis predicts that suppressing hypothalamic
KKp/NF-KB could reverse or prevent these diseases. The following three specific aims will be performed to
test this hypothesis: (1) determine the linkage of excessive nutrition with IKKp/NF-KB in the hypothalamus;
(2) elucidate the action of IKKp/NF-KB on hypothalamic insulin signaling; (3) assess metabolic outcomes of
heuronal IKKp/NF-KB manipulations in insulin-responsive hypothalamic nuclei and neurons. To achieve
these aims, our established in vitro and in vivo models and particularly the approaches of site-directed
transgenesis and conditional gene knockout will be empoyed to analyze IKKp/NF-KB, insulin signaling and
metabolic phenotypes. Completion of these aims will advance our knowledge about the brain pathogenesis
of obesity-T2D, provide a molecular basis for developing new therapeutic and preventive strategies, and also
establish a new model to study the nutrition-inflammation axis in the brain underlying nutritional diseases.
StatusFinished
Effective start/end date7/1/074/30/19

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $147,401.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $332,000.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $442,204.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $468,704.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $426,202.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $325,393.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $325,393.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $293,896.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $167.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $294,803.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $328,680.00

ASJC

  • Endocrinology, Diabetes and Metabolism
  • Genetics
  • Nephrology
  • Medicine(all)

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