PerspectiveCell Biology

Chewing the Fat--ACC and Energy Balance

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Science  30 Mar 2001:
Vol. 291, Issue 5513, pp. 2558-2559
DOI: 10.1126/science.1060277

Recent progress in understanding how energy balance and body weight are regulated [HN1] has been marked by the discovery of hormones, such as leptin [HN2], and the neural pathways operating downstream of these hormones that bring about physiological changes (1). These burgeoning discoveries have diverted attention away from more traditional studies of the intracellular metabolic machinery that controls the synthesis and oxidation of lipid fuels [HN3]. One component of this metabolic machinery, malonyl coenzyme A (CoA) [HN4], is a critical participant in the regulation of lipid fuel metabolism as it has effects on both fatty acid oxidation in the mitochondria and the synthesis of various lipids. Disturbances in malonyl CoA regulation leading to alterations in signal transduction may contribute to insulin resistance [HN5] (2) and obesity [HN6] (2, 3), although as yet the evidence for this is indirect. On page 2613 of this issue, Abu-Elheiga et al. [HN7] (4) now show that malonyl CoA in certain key tissues (such as, heart and skeletal muscle) [HN8] is a crucial regulator of fat metabolism and energy balance.

Malonyl CoA—synthesized by the enzyme acetyl CoA carboxylase (ACC) [HN9]—has two principal tasks in the cell. It provides acetyl groups that are incorporated into fatty acids during their synthesis and it inhibits the enzyme carnitine palmitoyltransferase [HN10], which controls transfer of long-chain fatty acyl CoA molecules to the mitochondria [HN11], where they are oxidized to provide energy (5). Increasing the fuel supply of muscle cells by treating them with glucose and insulin increases the concentration of malonyl CoA and diminishes fatty acid oxidation by increasing the activity of ACC2 [HN12] (also called ACCβ) the predominant ACC isoform in cardiac and skeletal muscle. Conversely, exercise lowers the concentration of malonyl CoA by activating an AMP-activated protein kinase [HN13] (AMPK), which phosphorylates and inhibits ACC2 (2).

Abu-Elheiga et al. address the question of whether malonyl CoA is a regulator of fat metabolism and energy balance by creating a mouse strain that lacks ACC2 (4). ACC1 (also called ACCα), the dominant isoform in liver and adipose tissue [HN14], is encoded by a separate gene, and is expressed normally in these mice. The ACC2-deficient mice showed a marked decrease in the concentration of malonyl CoA in skeletal muscle (30-fold) and heart muscle (10-fold) and a substantial increase in fatty acid oxidation in skeletal muscle. Furthermore, fatty acid stores in adipose tissue and liver, two organs in which ACC1 is the dominant isoform, were markedly decreased (in adipose tissue by 50%), despite normal concentrations of malonyl CoA. Fatty acids and glucose in plasma and glycogen in the liver were diminished by 20 to 30%. In addition, the ACC-deficient mice consumed 20 to 30% more food than wild-type mice, yet they maintained or, even more surprisingly, lost body weight, suggesting that they were expending energy at an increased rate. Finally, despite the depletion of their lipid stores, these mice appeared normal morphologically, grew at the expected rate, and bred normally. These findings raise three obvious questions: What accounts for the loss of fatty acid stores in adipose tissue and liver of the ACC-deficient mice? Why do these mice eat more? Why do they lose or at best maintain body weight despite an increase in food intake?

The authors speculate that the primary event initiating these changes is an increase in fatty acid oxidation in the mitochondria of muscle and liver cells. A decrease in a pool of malonyl CoA would release the block on carnitine palmitoyltransferase activity, increasing the transport of long-chain fatty acids into the mitochondria and promoting their oxidation to produce energy. How might a change in fatty acid oxidation in muscle and liver affect the energy balance of the entire body? The authors propose that increased food intake is caused by a 30% decrease in plasma leptin (a molecule that regulates hunger), which may be secondary to the decrease in fat tissue. However, this explanations does not address how an increase in fatty acid oxidation in muscle and liver signals fat cells (adipocytes) to increase the breakdown of fat stores (triglycerides), or why whole-body energy expenditure is enhanced, given that a low concentration of leptin would decrease energy expenditure. Furthermore, it is not clear from the data whether the increase in food intake was an early event, preceding the elevation of plasma leptin, or whether it occurred later, as the authors propose.

Alternatively, the observed changes may reflect a loss of ACC2 activity in tissues other than muscle. Previous work by Abu-Elheiga (6) suggests that ACC2 in skeletal muscle is associated with mitochondria and that the malonyl CoA that it generates (versus that produced by ACC1) is an important regulator of carnitine palmitoyltransferase and fatty acid oxidation [HN15]. Because some ACC2 may be present in cells in which ACC1 is the dominant isoform—such as pancreatic islets, human adipose tissue, and brain—it is possible that fatty acid oxidation and, secondarily, various signaling and downstream events are altered by loss of ACC2 in these or other tissues. Consistent with this notion are recent results suggesting that a pharmacologically induced increase in malonyl CoA in the hypothalamus [HN16] both decreases the expression of neuropeptide Y [HN17] and food intake and increases production of heat (thermogenesis) in obese mice (5). Thus, loss of ACC2 in hypothalamic neurons that regulate energy balance could alter energy intake and expenditure by modulating the production of malonyl CoA or another key metabolic intermediate. ACC has been detected in select neurons of the brain, notably in the arcuate nucleus of the hypothalamus (5), although which ACC isoforms are present in these neurons has not been determined.

Another very intriguing possibility is that the increased food intake and thermogenesis, and decreased adiposity of the ACC-deficient mice are caused by an increase in the expression of uncoupling protein-3 (UCP3), which exists exclusively in muscle (see the figure). UCP3 is a close relative of UCP1 [HN18], which is found solely in brown fat [HN19], and similarly appears to be important for energy balance and lipid metabolism (7). Transgenic mice engineered to overexpress UCP3 in skeletal muscle are hyperphagic (that is, they overeat), yet they weigh less than their wild-type littermates [HN20] (8). In addition, these mice show a striking decrease in fat tissue and have low glucose levels, as do the ACC-deficient mice. Intriguingly, activation of AMPK in muscle, whether by exercise or incubation with the AMPK activator 5-amino-imidazole 4-carboxamide riboside (AICAR), increases the expression of UCP3 within 1 to 2 hours (9). Because activation of AMPK in these situations is very rapid (seconds to minutes), as is ACC2 inhibition (2), it is conceivable that the increase in fatty acid oxidation in these muscles is responsible for increases in UCP3 mRNA and protein. That UCP3 expression in muscle is increased during starvation and other situations in which fatty acid oxidation is elevated is consistent with this notion, although in starvation, the increase in UCP3 is not sufficient to increase whole-body thermogenesis. The status of muscle UCP3 in ACC-deficient mice is eagerly awaited.

Eat more, weigh less.

Increased food intake and heat production in ACC2-deficient mice. (A) A decrease in malonyl CoA, induced by lack of ACC2, results in an increase in fatty acid oxidation and decreases in the production of lipid signaling molecules such as diacylglycerol (DAG). (B) In skeletal muscle, the lack of ACC2 may possibly increase heat production through an increase in the expression of UCP3. Secondary increases in food intake and the lipolysis of fat cells may reflect production of yet-to-be-identified signaling molecules that enable muscle to communicate with the central nervous system (CNS) and with adipose tissue. (C) A decrease in ACC2 in the CNS might contribute to the phenotype of ACC2-deficient mice through its effects on the brain, resulting in increased food intake and energy expenditure. Whether a decrease in leptin contributes to increased food intake in either (B) or (C) is unclear. SNS, sympathetic nervous system.

Finally, a number of studies provide evidence for cross talk between fat cells and other organs, most notably skeletal muscle and the central nervous system (10). Indeed, the discovery that adipocyte-derived molecules—such as leptin, tumor necrosis factor-α, gAcrp30 [HN21] (11), and most recently resistin [HN22] (12)—have systemic metabolic effects has firmly established the adipocyte as an endocrine organ. The results of Abu-Elheiga et al. and the findings in mice that overexpress UCP3 suggest that skeletal muscle could act in a similar manner to regulate whole-body energy homeostasis. Studies of altered signaling and gene transcription in muscle cells when fatty acid oxidation is increased or decreased, and an evaluation of whether and how these alterations are communicated to other organs are clearly in order.

The new work demonstrates that mice deficient in ACC2 have major alterations in systemic energy balance, with decreased body fat despite increased food intake. These findings provide important insights into the part played by malonyl CoA, the regulatory molecule produced by ACC2, in fatty acid oxidation in muscle and other cells. They also raise questions about the cellular sites and signal transduction pathways through which ACC2 exerts its newly identified systemic job. Whatever the mechanism, inhibition of ACC2 may be a plausible target for the design of new anti-obesity therapeutics.

HyperNotes Related Resources on the World Wide Web

General Hypernotes

The Academic Press Dictionary of Science and Technology includes definitions of cell biology terms.

The On-line Medical Dictionary is provided by CancerWEB.

P. Gannon's Cell & Molecular Biology Online is a collection of annotated links to Internet resources.

The Bio Netbook is a searchable database of Internet resources provided by the Institut Pasteur, Paris.

Biology Links are provided by the Department of Molecular and Cellular Biology, Harvard University.

BUBL LINK, a catalog of selected Internet resources covering all academic subject areas maintained by the Strathclyde University Library, UK, offers links to Internet resources on biochemistry and molecular biology.

The CMS Molecular Biology Resource is a compendium of electronic and Internet-accessible tools and resources for molecular biology, biotechnology, molecular evolution, biochemistry, and biomolecular modeling.

Online Mendelian Inheritance in Man (OMIM) is a database providing a catalog of human genes and genetic disorders authored and edited at Johns Hopkins University Medical School and developed for the Internet by the National Center for Biotechnology Information (NCBI).

GeneCards, a project of the Crown Human Genome Center and the Bioinformatics Unit at the Weizmann Institute of Science, is a database of human genes, their products, and their involvement in diseases, with links provided to other genome databases and resources.

Britannica.com provides Encyclopædia Britannica articles on biochemistry, cell biology, and metabolism.

The THCME Medical Biochemistry Page is provided by M. King, Terre Haute Center for Medical Education, IN.

The MIT Biology Hypertextbook includes a chapter on cell biology.

The On-Line Biology Book is provided by M. Farabee, Estrella Mountain Community College, Avondale, AZ.

NetBiochem offers a tutorial on fatty acid synthesis and modification and summary tables about lipid metabolism processes.

W. McClure and E. Grotzinger, Department of Biological Sciences, Carnegie-Mellon University, provide lecture notes for a biochemistry course.

C. Rinehart, Department of Biology, Western Kentucky University, offers lecture notes for a course on molecular and cell biology.

G. Gray, Department of Chemistry and Physics, Southwest Baptist University, Bolivar, MO, offers lecture notes for a biochemistry course. Lecture notes on fatty acid metabolism are included.

J. Franck, Department of Biology, Occidental College, Los Angeles, provides lecture notes for a biochemistry course. Presentations on fatty acid metabolism and fatty acid metabolism synthesis and controls are provided.

J. Illingworth, School of Biochemistry and Molecular Biology, University of Leeds, UK, provides lecture notes on metabolism.

L. Van Warren's Biochem Notebook Web site makes available an introduction to metabolism by D. DeLuca, Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences.

J. Diwan, Department of Biology, Rensselaer Polytechnic Institute, provides lecture notes for molecular biology courses on metabolism (part one and part two). Presentations on lipid catabolism and fatty acid synthesis are included.

The 29 May 1998 issue of Science had an article by S. Woods et al. titled “Signals that regulate food intake and energy homeostasis.”

Numbered Hypernotes

1. The Pathophysiology of the Digestive System hypertextbook by R. Bowen, Animal Reproduction and Biotechnology Laboratory, Colorado State University, includes a presentation titled “Control of food intake and body weight” and a presentation titled “Genetics of food intake, body weight and obesity.” D. Banks, Division of Physiology, Guy's, King's and St. Thomas' School of Biomedical Sciences, London, provides lecture notes on control mechanisms in energy balance. Floyd College, Rome, GA, makes available lecture notes by M. Windelspecht on metabolism and energy balance for a course on the principles of nutrition. The Department of Biology, Andrews University, Berrien Springs, MI, offers lecture notes on the regulation of metabolism for a physiology course. Zone Home, a Web resource for health information, makes available lecture notes on mammalian metabolic homeostasis by D. Walsh, Department of Biological Chemistry, University of California, Davis, School of Medicine. The April 1999 issue of Physiological Reviews had an article by E. Jéquier and L. Tappy titled “Regulation of body weight in humans.”

2. OMIM has an entry for leptin. Kimball's Biology Pages includes an introduction to leptin. R. Bowen's Pathophysiology of the Endocrine System includes a section on leptin. The 20 April 1999 issue of the Annals of Internal Medicine had an article by C. Mantzoros titled “The role of leptin in human obesity and disease: A review of current evidence.” The May 1998 issue of the Journal of Clinical Endocrinology & Metabolism had an article by J. Flier titled “What's in a name? In search of leptin's physiologic role.” The April 1997 issue of the Proceedings of the National Academy of Sciences had a commentary by Flier titled “Leptin expression and action: New experimental paradigms.” The November 1999 issue of Endocrinology had an article by R. Cone titled “The ups and downs of leptin action.” The 22 October 1998 issue of Nature had a review article by J. Friedman and J. Halaas titled “Leptin and the regulation of body weight in mammals.” The 10 March 2000 issue of Science had a news article by T. Gura titled “Tracing leptin's partners in regulating body weight.”

3. The THCME Medical Biochemistry Page includes sections on fatty acid synthesis and fatty acid oxidation. The Pathways section of the Biochemistry Web Pages of Mills College, Oakland, CA, includes summaries of the reactions of fatty acid oxidation and fatty acid biosynthesis. The Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, provides lecture notes on lipid metabolism for a medical biochemistry course; a section on regulation of fatty acid metabolism is included. K. Redding, Department of Chemistry, University of Alabama, offers lecture notes on fatty acid synthesis for a biochemistry course. R. Miesfeld, Department of Biochemistry and Molecular Biophysics, University of Arizona, presents lecture notes on fatty acid metabolism (part 1 and part 2) for a biochemistry course. The Centre for Life Sciences and Chemical Technology, Ngee Ann Polytechnic, Singapore, offers lecture notes on fatty acid metabolism for a course on analytical biochemistry. S. Stanforth, Division of Chemical Sciences, School of Applied and Molecular Sciences, University of Northumbria, Newcastle, UK, offers a presentation on the biosynthesis of fatty acids for a course on natural products chemistry. F. Leach, Department of Biochemistry & Molecular Biology, Oklahoma State University, makes available a student review article by B. Gardner on fatty acid synthesis prepared for a course on metabolism and its regulation.

4. The section on fatty acids in the Encyclopædia Britannica article on metabolism includes information about malonyl coenzyme A. S. Stanforth offers a presentation on malonyl coenzyme A for a course on natural products chemistry. R. Murphy, Department of Chemistry, New York University, offers an image of the structure of malonyl Coenzyme A for a biochemistry course.

5. OMIM provides information about insulin resistance. T. Dorsch's Diabetes Central offers a presentation on insulin resistance. The January 1999 issue of the American Journal of Physiology - Endocrinology and Metabolism had a review article by N. Ruderman et al. titled “Malonyl-CoA, fuel sensing, and insulin resistance” (2). The 22 September 2000 issue of Science had an Enhanced Perspective by M. Schwartz titled “Staying slim with insulin in mind.”

6. OMIM includes an entry about obesity. NCBI's Genes and Disease Web exhibit includes an introduction to obesity. The Society for Neuroscience offers a briefing on weight control and obesity. The Internet Journal of Academic Physician Assistants had an article (vol.1, no. 2, 1998) by D. Oeser titled “Obesity Part I: Epidemiology, etiology and pathophysiology, and nonpharmacotherapeutic treatments.” The August 1996 issue of Scientific American had an article by W. Gibbs titled “Gaining on fat.” The 30 June 2000 issue of Science had a news article by T. Gura titled “Enzyme blocker prompts mice to shed weight” about the research reported in that issue by T. Loftus et al. (titled “Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors”) (3). The 7 February 1997 issue had a news article by Gura titled “Obesity sheds its secrets.” About Obesity is an Internet resource for the public and professionals provided by the Donald B. Brown Research Chair on Obesity, Laval University, Quebec.

7. L. Abu-Elheiga, A. Abo-Hashema, and S. Wakil are in the Department of Biochemistry and Molecular Biology, Baylor College of Medicine. M. Matzuk is in the Department of Pathology, Baylor College of Medicine.

8. The Muscle Physiology Home Page, provided by the Muscle Physiology Laboratory at the University of California, San Diego, offers an introduction to muscle physiology and design; included are presentations on glucose metabolism and fat metabolism. J. Illingworth provides lecture notes on muscle structure and function. The University of Sheffield Medical Education Home Page provides a collection of lectures on muscle metabolism including a presentation on the regulation of muscle metabolism by E. Carey, Department of Molecular Biology and Biotechnology.

9. NebBiochem's fatty acid tutorial has a section on acetyl CoA carboxylase (ACC). OMIM provides information about ACC. The ENZYME database from the ExPASy Molecular Biology Server includes an entry for ACC. G. Schlink, Department of Biology and Environmental Health, Missouri Southern State College, Joplin, makes available a student presentation on ACC by R. Hudson, prepared for a genetics course.

10. OMIM has entries for carnitine palmitoyltransferase (CPT) and CPT deficiency. The Spiral Notebook, a collection of articles about CPT deficiency, includes an overview of CPT nomenclature and a presentation on the role of the CPT enzymes in mitochondrial metabolism. F. Leach provides a student review article by C. Ackerman on carnitine metabolism, which was prepared for a course on metabolism and its regulation.

11. Cells Alive! provides an introduction to mitochondria. M. Farabee's On-Line Biology Book has a section on mitochondria. Cell Biology Topics, provided by G. Childs, Department of Anatomy, University of Arkansas for Medical Sciences, includes a presentation on mitochondria. J. Illingworth makes available a presentation on mitochondria and oxidative phosphorylation.

12. OMIM has an entry for ACC2. The GeneCards database has entries with links for ACC2 and ACC1.

13. OMIM provides information about AMPK. The GeneCards database has an entry for AMPK. The MRC Clinical Sciences Centre, Hammersmith Hospital, London, offers a presentation on the research of D. Carling on cellular stress and AMPK. The July 1999 issue of the American Journal of Physiology - Endocrinology and Metabolism had a review article by W. Winder and D. Hardie titled “AMP-activated protein kinase, a metabolic master switch: Possible roles in Type 2 diabetes” with sections on AMPK structure and tissue distribution and regulation of AMPK activity.

14. The Academic Press Dictionary of Science and Technology provides a definition of adipose tissue. Britannica.com offers an Encyclopædia Britannica introduction to adipose cells and an article on the liver. An article on adipose tissue by A. Albright and J. Stern is included in the online Encyclopedia of Sports Medicine and Science. Jefferson Publishing at Thomas Jefferson University offers a tutorial on adipose tissue from a CD-ROM titled Histology: A Student's Guide to Microscopic Anatomy. Images of adipose tissue are provided for a course on mammalian histology taught by R. Wagner, Department of Biological Sciences, University of Delaware. The Veterinary Histology Atlas provided by the College of Veterinary Medicine, University of Illinois, offers annotated images of adipose tissue.

15. The 15 February 2000 issue of the Proceedings of the National Academy of Sciences had an article by L. Abu-Elheiga et al. titled “The subcellular localization of acetyl-CoA carboxylase 2” (6).

16. Britannica.com offers an Encyclopædia Britannica article on the hypothalamus. The Neuroscience Tutorial from the Washington University School of Medicine includes a presentation on the hypothalamus. The University of Massachusetts Medical School provides lecture notes on the hypothalamus for a course on mind, brain, and behavior.

17. OMIM has an entry for neuropeptide Y. R. Bowen's pathophysiology hypertextbook includes a section on neuropeptide Y.

18. OMIM has entries for uncoupling protein 3 (UPC3) and uncoupling protein 1 (UCP1). The GeneCards database offers entries with links for UCP3 and UCP1. Jackson Laboratory's Mouse Genomics Informatics database has entries for Ucp3 and Ucp1. InScight had a 17 February 1998 article about uncoupling proteins titled “Feverish fat genes.” The 1 March 2001 issue of the online journal Frontiers in Bioscience had a review article by N. Tsuboyama-Kasaoka and O. Ezaki titled “Mitochondrial uncoupling protein 3 (UCP3) in skeletal muscle.”

19. R. Bowen's pathophysiology hypertextbook has a section on brown adipose tissue.

20. Nature offers a Science Update by S.-Y. Thornhill about the uncoupling protein research of J. Clapham et al. (“Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean” in the 27 July 2000 issue) (8). BBC News had a 26 July 2000 feature by M. McGrath titled “Skinny mice defy obesity.”

21. The Academic Press Dictionary of Science and Technology defines and pronounces adipocyte. OMIM has an entry for tumor necrosis factor (TNF). The GeneCards database has an entry for TNF. H. Ibelgaufts' Cytokines Online Pathfinder Encyclopaedia (COPE) has an entry for TNF alpha. A presentation on the adipocyte on the laboratory home page of P. Scherer, Albert Einstein College of Medicine, includes a discussion of Acrp30 and TNF. The 13 February 2001 issue of the Proceedings of the National Academy of Sciences had an article about gAcrp30 research by J. Fruebis, T.-S. Tsao, S. Javorschi, D. Ebbets-Reed, M. Erickson, F. Yen, B. Bihain, and H. Lodish titled “Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.” H. Lodish, Whitehead Institute for Biomedical Research, offers a laboratory Web page with information about the group's research on Acrp30. BBC News had a 14 September 2000 feature titled “Fat ‘is an organ’ say scientists.”

22. OMIM has an entry for resistin. Nature had a 11 January 2001 online Feature of the Week titled “Resistin diabetes” about the 18 January 2001 research article by C. Steppan et al. (titled “The hormone resistin links obesity to diabetes”); the research is also discussed in a News and Views article by J. Flier and in a Science Update by D. Adam. DrKoop.com offers a 18 January 2001 news story about resistin by N. Charbonneau titled “Hormone may link obesity and diabetes.”

23. N. Ruderman is in the Diabetes and Metabolism Research Unit, Boston Medical Center, Boston University School of Medicine.

24. J. S. Flier is in the Department of Medicine, Beth Israel Deaconess Medical Center, Boston.

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