Hypothalamic dysfunction in obesity

Lynda M Williams*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

102 Citations (Scopus)


A growing number of studies have shown that a diet high in long chain SFA and/or obesity cause profound changes to the energy balance centres of the hypothalamus which results in the loss of central leptin and insulin sensitivity. Insensitivity to these important anorexigenic messengers of nutritional status perpetuates the development of both obesity and peripheral insulin insensitivity. A high-fat diet induces changes in the hypothalamus that include an increase in markers of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, autophagy defect and changes in the rate of apoptosis and neuronal regeneration. In addition, a number of mechanisms have recently come to light that are important in the hypothalamic control of energy balance, which could play a role in perpetuating the effect of a high-fat diet on hypothalamic dysfunction. These include: Reactive oxygen species as an important second messenger, lipid metabolism, autophagy and neuronal and synaptic plasticity. The importance of nutritional activation of the Toll-like receptor 4 and the inhibitor of NF-κB kinase subunit β/NK-κB and c-Jun amino-terminal kinase 1 inflammatory pathways in linking a high-fat diet to obesity and insulin insensitivity via the hypothalamus is now widely recognised. All of the hypothalamic changes induced by a high-fat diet appear to be causally linked and inhibitors of inflammation, ER stress and autophagy defect can prevent or reverse the development of obesity pointing to potential drug targets in the prevention of obesity and metabolic dysfunction.

Original languageEnglish
Pages (from-to)521-533
Number of pages13
JournalProceedings of the Nutrition Society
Issue number4
Early online date6 Jun 2012
Publication statusPublished - 1 Nov 2012


  • high-fat diet
  • hypothalamus
  • inflammation
  • neuronal and synaptic plasticity
  • obesity


Dive into the research topics of 'Hypothalamic dysfunction in obesity'. Together they form a unique fingerprint.

Cite this