Hypothalamic dysfunction in obesity

• Published in: Proceedings of the Nutrition Society Vol. 71; no. 4; pp. 521 - 533
• Main Author: Williams, Lynda M.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.11.2012
• Subjects: 70th Anniversary Conference on ‘Body weight regulation – food, gut and brain signalling’; Animals; apoptosis; autophagy; Biological and medical sciences; Body fat; Diabetes; Diet; Diet, High-Fat - adverse effects; Dietary Fats - adverse effects; Dietary Fats - metabolism; drugs; endoplasmic reticulum; Energy; Energy balance; Energy Metabolism - physiology; Feeding. Feeding behavior; Food; Fundamental and applied biological sciences. Psychology; Glucose; high fat diet; Hormones; Human subjects; Humans; Hypothalamus; Hypothalamus - metabolism; Hypothalamus - physiopathology; Inflammation; Inflammation - metabolism; Insulin; Insulin Resistance; Kinases; leptin; lipid metabolism; Lipid Metabolism - physiology; Lipids; Metabolism; Neuronal Plasticity; neurons; neuroplasticity; Nutrition; Nutritional Status; Obesity; Obesity - metabolism; Obesity - physiopathology; Oxidative Stress; reactive oxygen species; Signal Transduction; Symposium III: Brain signalling and onward communications; Toll-like receptor 4; transcription factor NF-kappa B; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Weight control; United Kingdom > UK; United States > US; Obesity; Inflammation; Hypothalamus; High-fat diet; Neuronal and synaptic plasticity; Central nervous system; Nutrition disorder; Feeding; Encephalon; Vertebrata; Mammalia; Diet; Dysfunction; Synaptic plasticity; Fat; Nutritional status
• ISSN: 0029-6651; 1475-2719; 1475-2719
• DOI: 10.1017/S002966511200078X

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.