A new article out in the Journal of Clinical Investigation identifies a new role for the enzyme CPT-1 in weight regulation; the link and a commentary are below. (all JCI commentary and articles are freely available at http://www.jci.org/ if you want to look at the full original article). This enzyme is important in fatty acid oxidation and has been studied primarily with respect to fatty acid metabolism, and not how that might influence feeding. CPT-1 has not yet been studied in PWS– probably because it has not really been implicated in feeding until this article.
This study goes along with that relatively new concept of ‘hypothalamic sensing of nutrients’ – where the hypothalamus of the brain actively senses how much glucose and fatty acids are around, and modifies the food intake/food inhibitory hormone release accordingly. Rats that are overfed fat lose this ability to sense that there's too much lipids around. CPT-1 activity is apparently responsible for this lack of responsiveness; when CPT-1 activity in the brain is blocked, the ability of the rats to 'notice' the circulating lipids is restored.
Hypothalamic sensing of nutrients is an area of very active investigation and one that potentially will open up some new treatment options. The important point (to me) is that the brain can respond rapidly to perceived changes in nutrients. This suggests that by altering nutrients in the blood system, you might be able to alter the feeding signals from the brain.
One of the new projects FPWR is currently funding (Dr. O’Rahilly) will look at hormonal and nutritional signals in the hypothalamus as relates to expression of PWS-region genes. His project doesn’t look at this particular aspect of nutrient sensing by hypothalamus, but it will look at another aspect of nutrient sensing and PWS region genes.
Journal of Clinical Investigation Editorial Summary:
Rats presented with a lard-supplemented diet double their caloric intake and develop severe hepatic insulin resistance within 3 days. Using this as a model of human obesity, Pocai and colleagues further investigate how to trick overfed rats into eating less (pages 1081-1091). They exploit the finding that hypothalamic metabolism of fatty acids can control feeding and glucose metabolism. Central administration of long-chain fatty acids (LCFAs) inhibits feeding in normal but not in overfed rats. Here the authors show that an increase in circulating lipids fails to increase the levels of esterified LCFAs in the mediobasal hypothalamus in overfed rats and that the activity of liver enzyme carnitine palmitoyltransferase-1 (CPT1) is selectively increased in the arcuate nuclei of overfed rats. Central inhibition of CPT1 decreased food intake and restored hypothalamic LCFA regulation. This work provides the first direct demonstration for impaired sensing of lipids in overfed rats and demonstrates that restoring the hypothalamic levels of esterified LCFAs via inhibition of CPT1 is sufficient to normalize food intake, body weight gain, and glucose homeostasis. A strategy designed to restore lipid sensing within the arcuate nuclei of the hypothalamus could potentially be an obesity treatment.
Abstract:
Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. A Pocai, T K.T. Lam, S Obici, R Gutierrez-Juarez, E. D. Muse, A Arduini and L Rossetti J Clin Invest. 2006 Apr;116(4):1081-91.
