Carnitine palmitoyltransferase-1 (CPT-1) activity stimulation by cerulenin via sympathetic nervous system activation overrides cerulenin's peripheral effect.
To clarify the paradoxic effects of cerulenin, namely its in vitro inhibitory effects on fat catabolism and its in vivo reduction of fat mass, we studied the in vivo and in vitro effects of cerulenin on carnitine palmitoyltransferase-1 (CPT-1) activity, the rate-limiting enzyme of fatty acid oxidation. A single ip injection of cerulenin significantly reduced body weight and increased core temperature without significantly reducing food intake. In situ hybridization study revealed that a single injection of cerulenin did not affect the expression of orexigenic neuropeptide mRNA. Cerulenin's effect on CPT-1 activity was biphasic in the liver and muscle: early suppression during the first 1 h and late stimulation in the 3-5 h after ip treatment. In vitro cerulenin treatment reduced CPT-1 activity, which was overcome by cotreating with catecholamine. Intracerebroventricular injection of cerulenin increased CPT-1 activity significantly in soleus muscle, and this effect was sustained for up to 3 h. Pretreatment with alpha-methyl-p-tyrosine inhibited the cerulenin-induced increase in core temperature and the late-phase stimulating effect of cerulenin on CPT-1 activity. In adrenalectomized mice, cerulenin also increased the activity. In vivo cerulenin treatment enhanced muscle CPT-1 activity in monosodium glutamate-treated arcuate nucleus lesioned mice but not in gold thioglucose-treated ventromedial hypothalamus lesioned mice. These findings suggest that cerulenin-induced late-phase stimulating effects on CPT-1 activity and energy expenditure is mediated by the activation of innervated sympathetic nervous system neurons through the firing of undefined neurons of the ventromedial hypothalamus, rather than the arcuate nucleus.
Jin
Yong-Jun
YJ
Division of Endocrinology, Department of Internal Medicine, College of Medicine, and Brain Korea 21 Project for Medical Sciences, Yonsei University, Seoul, Korea.
Li
Song-Zhe
SZ
Zhao
Zheng-Shan
ZS
An
Juan Ji
JJ
Kim
Ryang Yeo
RY
Kim
Yoo Mee
YM
Baik
Ja-Hyun
JH
Lim
Sung-Kil
SK
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D002569:Cerulenin / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000235:genetics; D011247:Pregnancy; D013564:Sympathetic Nervous System / Q000201:enzymology*
D000935:Antifungal Agents; D009479:Neuropeptides; D002569:Cerulenin; D002334:Carnitine O-Palmitoyltransferase