Pharmacological stimulation of brain carnitine palmitoyl-transferase-1 decreases food intake and body weight

被引：44

作者：

Aja, Susan ^{[1
]}

Landree, Leslie E. ^{[2
]}

Kleman, Amy M. ^{[2
]}

Medghalchi, Susan M. ^{[4
]}

Vadlamudi, Aravinda ^{[4
]}

McFadden, Jill M. ^{[5
]}

Aplasca, Andrea ^{[1
]}

Hyun, Jayson ^{[1
]}

Plummer, Erica ^{[1
]}

Daniels, Khadija ^{[1
]}

Kemm, Matthew ^{[1
]}

Townsend, Craig A. ^{[5
]}

Thupari, Jagan N. ^{[3
]}

Kuhajda, Francis P. ^{[3
]}

Moran, Timothy H. ^{[1
]}

Ronnett, Gabriele V. ^{[2
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[4] FASgen, Baltimore, MD USA

[5] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA

来源：

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY | 2008年 / 294卷 / 02期

关键词：

central nervous system; fatty acid metabolism; energy intake; AMP-activated protein kinase;

D O I：

10.1152/ajpregu.00862.2006

中图分类号：

Q4 [生理学];

学科分类号：

071003 ;

摘要：

Inhibition of brain carnitine palmitoyl-transferase-1 (CPT-1) is reported to decrease food intake and body weight in rats. Yet, the fatty acid synthase (FAS) inhibitor and CPT-1 stimulator C75 produces hypophagia and weight loss when given to rodents intracerebroventricularly (icv). Thus roles and relative contributions of altered brain CPT-1 activity and fatty acid oxidation in these phenomena remain unclarified. We administered compounds that target FAS or CPT-1 to mice by single icv bolus and examined acute and prolonged effects on feeding and body weight. C75 decreased food intake rapidly and potently at all doses (1-56 nmol) and dose dependently inhibited intake on day 1. Dose-dependent weight loss on day 1 persisted through 4 days of postinjection monitoring. The FAS inhibitor cerulenin produced dose-dependent (560 nmol) hypophagia for 1 day, weight loss for 2 days, and weight regain to vehicle control by day 3. The CPT-1 inhibitor etomoxir (32, 320 nmol) did not alter overall day 1 feeding. However, etomoxir attenuated the hypophagia produced by C75, indicating that CPT-1 stimulation is important for C75's effect. A novel compound, C89b, was characterized in vitro as a selective stimulator of CPT-1 that does not affect fatty acid synthesis. C89b (100, 320 nmol) decreased feeding in mice for 3 days and produced persistent weight loss for 6 days without producing conditioned taste aversion. Similarly, intraperitoneal administration decreased feeding and body weight without producing conditioned taste aversion. These results suggest a role for brain CPT-1 in the regulation of energy balance and implicate CPT-1 stimulation as a pharmacological approach to weight loss.

引用

页码：R352 / R361

页数：10

共 51 条

[51] C75 [4-methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic acid] activates carnitine palmitoyltransferase-1 in isolated mitochondria and intact cells without displacement of bound malonyl CoA [J].

Yang, NY ;

Kays, JS ;

Skillman, TR ;

Burris, L ;

Seng, TW ;

Hammond, C .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 312 (01) :127-133

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