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The Brain-Specific Carnitine Palmitoyltransferase-1C Regulates Energy Homeostasis Michael J

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The Brain-Specific Carnitine Palmitoyltransferase-1C Regulates Energy Homeostasis Michael J The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis Michael J. Wolfgang*†, Takeshi Kurama†‡, Yun Dai*, Akira Suwa‡, Makoto Asaumi‡, Shun-ichiro Matsumoto‡, Seung Hun Cha*, Teruhiko Shimokawa‡, and M. Daniel Lane*§ *Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and ‡Molecular Medicine Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan Contributed by M. Daniel Lane, March 17, 2006 Fatty acid synthesis in the central nervous system is implicated in the physiologically regulated by fasting and refeeding (18). However, control of food intake and energy expenditure. An intermediate in neither the target nor the molecular mechanism of malonyl- this pathway, malonyl-CoA, mediates these effects. Malonyl-CoA is CoA’s action in the CNS has been elucidated. an established inhibitor of carnitine palmitoyltransferase-1 (CPT1), an A known target of malonyl-CoA in liver and muscle is carnitine outer mitochondrial membrane enzyme that controls entry of fatty palmitoyltransferase-1 (CPT1; palmitoyl-CoA:L-carnitine O- acids into mitochondria and, thereby, fatty acid oxidation. CPT1c, a palmitoyltransferase, EC 2.3.1.21), which catalyzes the rate-limiting brain-specific enzyme with high sequence similarity to CPT1a (liver) step of ␤-oxidation by translocating fatty acids across the mito- and CPT1b (muscle) was recently discovered. All three CPTs bind chondrial membranes. Malonyl-CoA inhibits CPT1 action, thus malonyl-CoA, and CPT1a and CPT1b catalyze acyl transfer from blocking the oxidation of fatty acids during times of fatty acid various fatty acyl-CoAs to carnitine, whereas CPT1c does not. These synthesis and energy surplus (19–21). Pharmacologic inhibition of findings suggest that CPT1c has a unique function or activation CPT1 in the CNS inhibits food intake, suggesting malonyl-CoA may mechanism. We produced a targeted mouse knockout (KO) of CPT1c suppress food intake through a CNS-expressed CPT1 (22). Re- to investigate its role in energy homeostasis. CPT1c KO mice have cently, it was shown that mammals express another CPT1, i.e., lower body weight and food intake, which is consistent with a role CPT1c, which is brain-specific and has high homology to liver as an energy-sensing malonyl-CoA target. Paradoxically, CPT1c KO CPT1a and muscle CPT1b (23). CPT1c is expressed exclusively in mice fed a high-fat diet are more susceptible to obesity, suggesting the CNS with high local expression in areas critical for the regu- that CPT1c is protective against the effects of fat feeding. CPT1c KO lation of energy homeostasis (ref. 22; Y.D., M.J.W., and M.D.L, mice also exhibit decreased rates of fatty acid oxidation, which may unpublished results). CPT1c binds malonyl-CoA but, unlike contribute to their increased susceptibility to diet-induced obesity. CPT1a, is unable to catalyze acyl transfer from fatty acyl-CoAs to These findings indicate that CPT1c is necessary for the regulation of carnitine. To assess the physiological role of this putative enzyme energy homeostasis. in energy homeostasis, we produced CPT1c knockout (KO) mice. We found that disruption of the CPT1c gene leads to decreased ͉ ͉ ͉ ͉ acetyl-CoA carboxylase fatty acid synthase food intake malonyl-CoA food intake and body weight. Paradoxically, CPT1c KO mice are obesity exceptionally susceptible to diet-induced obesity on a high-fat diet. ody weight is maintained by regulating food intake and energy Results Bexpenditure. This balance is monitored by the central nervous CPT1c Binds Malonyl-CoA but Does Not Catalyze Fatty Acyl Transfer to system (CNS) in response to cytokine and endocrine signals, Carnitine. CPT1c was identified and cloned based on homology including leptin, ghrelin, obestatin, insulin, cholecystokinin, and searching of EST databases with known CPT sequences (23). peptide YY secreted by peripheral tissues. Concomitantly, parallel CPT1c is apparently a relatively recent gene duplication, because it pathways in the CNS regulate energy balance by monitoring the has been found only in mammals. CPT1c protein was shown to be availability of neuronal energy-rich metabolic substrates. Integra- expressed exclusively in the brain (23), whereas CPT1a had limited tion of these signals occurs in the hypothalamus and, ultimately, in expression in the brain, and CPT1b was not expressed (ref. 22; Y.D. higher brain centers where feeding behavior and energy expendi- and M.D.L, unpublished data). CPT1c has a high degree of primary ture are adjusted. Two primary indicators of energy surplus, glucose amino acid similarity and identity to CPT1a and CPT1b (Fig. 1A). and fatty acids, are also monitored by subsets of hypothalamic Based on this high degree of sequence similarity and in silico neurons that modulate feeding behavior and energy expenditure modeling, it was classified as a CPT1. However, whereas CPT1a was (1). Fatty acids (2) and de novo fatty acid synthesis from glucose (3) able to catalyze palmitoyl transfer from palmitoyl-CoA to carnitine are known to mediate these effects. Indeed, food intake and body in vitro, CPT1c and the inactive mutants of CPT1a (H473A) and weight have been shown to be altered by manipulating the activities CPT1c (H470A) were not (Fig. 1B). This finding agrees with of the enzymes involved in fatty acid synthesis, e.g., fatty acid previous data using medium, long, and very long chain acyl-CoAs synthase (FAS) (3), malonyl-CoA decarboxylase (4, 5), acetyl-CoA and yeast-expressed CPT1a and CPT1c (23). We have extended the carboxylase (ACC) (6, 7), stearoyl-CoA desaturase (8, 9), and Ј analysis to test acyl-CoA thioesters of various chain lengths and 5 -AMP kinase (10, 11). saturations. Acyl-CoAs were enzymatically synthesized from the Inhibition of FAS in the CNS, for example, reduces body corresponding free fatty acid by using Pseudomonas acyl-CoA weight by rapidly provoking a reduction in food intake and an synthetase. We expressed the CPT1 isoforms and isolated mito- increase in peripheral energy expenditure (3, 12). This inhibition can reverse the weight gain caused by diet-induced obesity (13, ͞ ͞ 14) or mutations in leptin (ob ob) or its receptor (db db) (3, 15), Conflict of interest statement: No conflicts declared. suggesting that it acts independently of STAT3, which is known Abbreviations: ACC, acetyl-CoA carboxylase; CPT, carnitine palmitoyltransferase; FAS, fatty to be essential for leptin’s action (16, 17). Inhibition of FAS acid synthase; KO, knockout. increases the level of its substrate, malonyl-CoA, in the hypo- †M.J.W. and T.K. contributed equally to this work. thalamus (18). The formation of malonyl-CoA from acetyl-CoA §To whom correspondence should be addressed at: Department of Biological Chemistry, catalyzed by ACC is the primary regulatory step in fatty acid Johns Hopkins University School of Medicine, 725 North Wolfe Street, 512 WBSB, Balti- synthesis. There is now compelling evidence that malonyl-CoA more, MD 21205. E-mail: [email protected]. is a signaling mediator of energy balance in the CNS and is © 2006 by The National Academy of Sciences of the USA 7282–7287 ͉ PNAS ͉ May 9, 2006 ͉ vol. 103 ͉ no. 19 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0602205103 Downloaded by guest on September 25, 2021 Table 1. Carnitine acyltransferase activity using a diverse array of fatty acyl-CoA derivatives Fatty acid CPT1c CPT1a 6:0 ϪϪ 12:0 Ϫϩϩ 12:1 (11) Ϫϩϩ 13:1 (12) Ϫϩϩ 14:0 Ϫϩϩ 16:0 Ϫ ϩϩϩ 16:1 (7) Ϫ ϩϩϩ 17:0 Ϫ ϩϩϩ 18:1 (9) Ϫ ϩϩϩ 18:3 (9, 12, 15) Ϫϩϩ 20:3 (11, 14, 17) ϪϪ 20:4 (8, 11, 14, 17) ϪϪ 20:5 (5, 8, 11, 14, 17) ϪϪ 22:5 (7, 10, 13, 16, 19) ϪϪ 14:1 (9) Ϫ ϩϩϩ 14:1 (9, trans) Ϫϩϩ 15:1 (10) Ϫ ϩϩϩ Fig. 1. Comparison of amino acid sequence and functional properties of 18:2 (9, 12) Ϫϩ CPT1a and CPT1c. (A) Amino acid sequence identity and similarity comparison 18:3 (6, 9, 12) Ϫ ϩϩϩ between CPT1a, CPT1b, and CPT1c. (B) Mitochondria from 293 T cells trans- 20:3 (8, 11, 14) ϪϪ fected with expression vectors for CPT1a, CPT1a (H473A), CPT1c, or CPT1c 20:4 (5, 8, 11, 14) ϪϪ (H470A) were used in carnitine acyltransferase assays with palmitoyl-CoA (75 16:1 (9, trans) Ϫ ϩϩϩ ␮M) as a substrate. ‘‘mg’’ refers to mitochondrial protein. (C) Concentration 17:1 (10) Ϫ ϩϩϩ dependence of malonyl-CoA binding to CPT1c. (D) Comparison of malonyl- 18:1 (11) Ϫϩϩ CoA binding to CPT1a and CPT1c. 18:1 (11, trans) Ϫ ϩϩϩ 18:1 (9) 12-OH ϪϪ 20:4 (5, 8, 11, 14) ϪϪ chondria from mammalian cells to more closely model their in vivo 16:1 (9, trans) Ϫ ϩϩϩ environment. All were tested for acyl transfer to carnitine catalyzed 17:1 (10) Ϫ ϩϩϩ by CPT1a and CPT1c. We have been unable to detect transfer 18:1 (11) Ϫϩϩ to carnitine in vitro from any acyl-CoA tested by using CPT1c 18:1 (11, trans) Ϫ ϩϩϩ (Table 1). 18:1 (9) 12-OH ϪϪ ϪϪ Hypothalamic malonyl-CoA is known to mediate food intake and 24:1 (15) 20:3 (5, 8, 11) ϪϪ energy expenditure. The molecular target of malonyl-CoA in the 18:1 (6) Ϫϩ hypothalamus is not known, but CPT1c is a provocative candidate, 18:1 (6, trans) Ϫ ϩϩϩ given that it is brain-specific and is highly expressed in regions of the 20:1 (8) ϪϪ hypothalamus known to mediate energy homeostasis (ref. 23; Y.D. 20:1 (5) ϪϪ and M.D.L., unpublished data). Malonyl-CoA indeed binds to 10:0 2-OH ϪϪ ϪϪ CPT1c with a Kd similar to that of CPT1a (Fig. 1 C and D) (23). 12:0 2-OH 14:0 2-OH ϪϪ Importantly, the CPT1c Kd (Ϸ0.3 ␮M) is within the dynamic range of hypothalamic (malonyl-CoA) in fasted and refed states (18).
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