Research Notes: Hypothalamus

J Clin Invest. 2006 Apr.
Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats.
Pocai A, Lam TK, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A, Rossetti L.
Department of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, New York, New York, USA.
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Short-term overfeeding blunts the central effects of fatty acids on food intake and glucose production. This acquired defect in nutrient sensing could contribute to the rapid onset of hyperphagia and insulin resistance in this model. Here we examined whether central inhibition of lipid oxidation is sufficient to restore the hypothalamic levels of long-chain fatty acyl-CoAs (LCFA-CoAs) and to normalize food intake and glucose homeostasis in overfed rats. To this end, we targeted the liver isoform of carnitine palmitoyltransferase-1 (encoded by the CPT1A gene) by infusing either a sequence-specific ribozyme against CPT1A or an isoform-selective inhibitor of CPT1A activity in the third cerebral ventricle or in the mediobasal hypothalamus (MBH). Inhibition of CPT1A activity normalized the hypothalamic levels of LCFA-CoAs and markedly inhibited feeding behavior and hepatic glucose fluxes in overfed rats. Thus central inhibition of lipid oxidation is sufficient to restore hypothalamic lipid sensing as well as glucose and energy homeostasis in this model and may be an effective approach to the treatment of diet-induced obesity and insulin resistance.

Nat Med. 2003 Jun.
Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production.
Obici S, Feng Z, Arduini A, Conti R, Rossetti L.
Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, USA.

The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid (LCFA) entry into mitochondria, where the LCFAs undergo beta-oxidation. To investigate the mechanism(s) by which central metabolism of lipids can modulate energy balance, we selectively reduced lipid oxidation in the hypothalamus. We decreased the activity of CPT1 by administering to rats a ribozyme-containing plasmid designed specifically to decrease the expression of this enzyme or by infusing pharmacological inhibitors of its activity into the third cerebral ventricle. Either genetic or biochemical inhibition of hypothalamic CPT1 activity was sufficient to substantially diminish food intake and endogenous glucose production. These results indicated that changes in the rate of lipid oxidation in selective hypothalamic neurons signaled nutrient availability to the hypothalamus, which in turn modulated the exogenous and endogenous inputs of nutrients into the circulation.

Neurosci Lett. 1994 Jan 3.
Stimulation of gonadotropin-releasing hormone secretion by acetyl-L-carnitine in hypothalamic neurons and GT1 neuronal cells.
Krsmanovic LZ, Virmani MA, Stojilkovic SS, Catt KJ.
Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD.

Pulsatile gonadotropin-releasing hormone (GnRH) secretion from perifused hypothalamic cells and GT1-1 neuronal cells was significantly increased after culture in medium containing 100 microM acetyl-L-carnitine (ALC). This action of ALC was largely due to an increase in the spike amplitude of GnRH release. In addition, the receptor-mediated release of GnRH by N-methyl-D-aspartic acid and endothelin was significantly increased in perifused cells cultured in ALC-enriched medium. Stimulatory effects of ALC on basal, high K(+)- and agonist-induced GnRH release were also observed during long-term culture of primary hypothalamic neurons. Similar effects of ALC were evident in cultured GT1-1 cells and were accompanied by a significant increase in cell number. These observations in normal and transformed GnRH neurons demonstrate that ALC promotes the growth and secretory activity of neuropeptide-producing cells of the hypothalamus.