Molecular disruption of hypothalamic nutrient sensing induces obesity
Abstract
The sensing of circulating nutrients within the mediobasal hypothalamus may be critical for energy homeostasis. To induce a sustained impairment in hypothalamic nutrient sensing, adeno-associated viruses (AAV) expressing malonyl-coenzyme A decarboxylase (MCD; an enzyme involved in the degradation of malonyl coenzyme A) were injected bilaterally into the mediobasal hypothalamus of rats. MCD overexpression led to decreased abundance of long-chain fatty acyl-coenzyme A in the mediobasal hypothalamus and blunted the hypothalamic responses to increased lipid availability. The enhanced expression of MCD within this hypothalamic region induced a rapid increase in food intake and progressive weight gain. Obesity was sustained for at least 4 months and occurred despite increased plasma concentrations of leptin and insulin. These findings indicate that nutritional modulation of the hypothalamic abundance of malonyl-coenzyme A is required to restrain food intake and that a primary impairment in this central nutrient-sensing pathway is sufficient to disrupt energy homeostasis and induce obesity.
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Reducing hypothalamic malonyl CoA levels causes obesity and insulin resistance.
“pharmacological interventions that reduce hypothalamic malonyl CoA levels cause obesity and insulin resistance (79).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [79]
Cites
Positional cloning of the mouse obese gene and its human homologue
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994) · Nature · doi:10.1038/372425a0 · Cited by 13,419 · see citing works
Central nervous system control of food intake
Schwartz, M. W., Woods, S. C., Porte, D., Seeley, R. J., & Baskin, D. G. (2000) · Nature · doi:10.1038/35007534 · Cited by 6,451 · see citing works
Weight-Reducing Effects of the Plasma Protein Encoded by the <i>obese</i> Gene
Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., Lallone, R. L., Burley, S. K., & Friedman, J. M. (1995) · Science · doi:10.1126/science.7624777 · Cited by 4,451 · see citing works
Congenital leptin deficiency is associated with severe early-onset obesity in humans
Montague, C. T., Farooqi, I. S., Whitehead, J. P., Soos, M. A., Rau, H., Wareham, N. J., Sewter, C. P., Digby, J. E., Mohammed, S. N., Hurst, J. A., et al. (1997) · Nature · doi:10.1038/43185 · Cited by 2,936 · see citing works
A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction
Clément, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., Gourmelen, M., Dina, C., Chambaz, J., Lacorte, J.-M., et al. (1998) · Nature · doi:10.1038/32911 · Cited by 2,346 · see citing works
Abnormal splicing of the leptin receptor in diabetic mice
Lee, G.-H., Proenca, R., Montez, J. M., Carroll, K. M., Darvishzadeh, J. G., Lee, J. I., & Friedman, J. M. (1996) · Nature · doi:10.1038/379632a0 · Cited by 2,327 · see citing works
Role of Brain Insulin Receptor in Control of Body Weight and Reproduction
Brüning, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., Klein, R., Krone, W., Müller-Wieland, D., & Kahn, C. R. (2000) · Science · doi:10.1126/science.289.5487.2122 · Cited by 2,235 · see citing works
AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus
Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y.-B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferré, P., Birnbaum, M. J., et al. (2004) · Nature · doi:10.1038/nature02440 · Cited by 1,637 · see citing works
McGarry, J. D. (2002) · Diabetes · doi:10.2337/diabetes.51.1.7 · Cited by 1,435 · see citing works
Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons
Woods, S. C., Lotter, E. C., McKay, L. D., & Porte, D. (1979) · Nature · doi:10.1038/282503a0 · Cited by 1,114 · see citing works
Flier, J. S. (2004) · Cell · doi:10.1016/s0092-8674(03)01081-x · Cited by 1,105 · see citing works
Phenotypes of Mouse diabetes and Rat fatty Due to Mutations in the OB (Leptin) Receptor
Chua, S. C., Chung, W. K., Wu-Peng, X. S., Zhang, Y., Liu, S.-M., Tartaglia, L. A., & Leibel, R. L. (1996) · Science · doi:10.1126/science.271.5251.994 · Cited by 1,071 · see citing works
Reduced Food Intake and Body Weight in Mice Treated with Fatty Acid Synthase Inhibitors
Loftus, T. M., Jaworsky, D. E., Frehywot, G. L., Townsend, C. A., Ronnett, G. V., Lane, M. D., & Kuhajda, F. P. (2000) · Science · doi:10.1126/science.288.5475.2379 · Cited by 1,004 · see citing works
Hypothalamic insulin signaling is required for inhibition of glucose production
Obici, S., Zhang, B. B., Karkanias, G., & Rossetti, L. (2002) · Nature Medicine · doi:10.1038/nm1202-798 · Cited by 904 · see citing works
Self-citationContinuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2
Abu-Elheiga, L., Matzuk, M. M., Abo-Hashema, K. A. H., & Wakil, S. J. (2001) · Science · doi:10.1126/science.1056843 · Cited by 903 · see citing works
Diabetes, Obesity, and the Brain
Schwartz, M. W., & Porte, D. (2005) · Science · doi:10.1126/science.1104344 · Cited by 841 · see citing works
Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G., Baskin, D. G., & Rossetti, L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-861 · Cited by 719 · see citing works
Self-citationFriedman, J. M. (2000) · Nature · doi:10.1038/35007504 · Cited by 701 · see citing works
Central Administration of Oleic Acid Inhibits Glucose Production and Food Intake
Obici, S., Feng, Z., Morgan, K., Stein, D., Karkanias, G., & Rossetti, L. (2002) · Diabetes · doi:10.2337/diabetes.51.2.271 · Cited by 654 · see citing works
Self-citationHypothalamic KATP channels control hepatic glucose production
Pocai, A., Lam, T. K. T., Gutierrez-Juarez, R., Obici, S., Schwartz, G. J., Bryan, J., Aguilar-Bryan, L., & Rossetti, L. (2005) · Nature · doi:10.1038/nature03439 · Cited by 645 · see citing works
Self-citationDecreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G. B., et al. (2002) · Nature Neuroscience · doi:10.1038/nn861 · Cited by 572 · see citing works
Self-citationObici, S., Feng, Z., Arduini, A., Conti, R., & Rossetti, L. (2003) · Nature Medicine · doi:10.1038/nm873 · Cited by 548 · see citing works
Self-citationHypothalamic sensing of fatty acids
Lam, T. K. T., Schwartz, G. J., & Rossetti, L. (2005) · Nature Neuroscience · doi:10.1038/nn1456 · Cited by 478 · see citing works
Self-citationAMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome
Ruderman, N., & Prentki, M. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1344 · Cited by 451 · see citing works
An, J., Muoio, D. M., Shiota, M., Fujimoto, Y., Cline, G. W., Shulman, G. I., Koves, T. R., Stevens, R., Millington, D., & Newgard, C. B. (2004) · Nature Medicine · doi:10.1038/nm995 · Cited by 450 · see citing works
Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis
Lam, T. K. T., Pocai, A., Gutierrez-Juarez, R., Obici, S., Bryan, J., Aguilar-Bryan, L., Schwartz, G. J., & Rossetti, L. (2005) · Nature Medicine · doi:10.1038/nm1201 · Cited by 432 · see citing works
Self-citationLeptin selectively decreases visceral adiposity and enhances insulin action
Barzilai, N., Wang, J., Massilon, D., Vuguin, P., Hawkins, M., & Rossetti, L. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119865 · Cited by 335 · cited 1× · see citing works
“Body composition was assessed as previously describe”
Self-citationEffect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats.
Rossetti, L., Shulman, G. I., Zawalich, W. S., & DeFronzo, R. A. (1987) · Journal of Clinical Investigation · doi:10.1172/jci113157 · Cited by 330 · see citing works
Self-citationHypothalamic malonyl-CoA as a mediator of feeding behavior
Hu, Z., Cha, S. H., Chohnan, S., & Lane, M. D. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834402100 · Cited by 272 · see citing works
McGarry, J., Stark, M. J., & Foster, D. W. (1978) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)34394-6 · Cited by 188 · see citing works
Rossetti, L., Giaccari, A., Barzilai, N., Howard, K., Sebel, G., & Hu, M. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116681 · Cited by 186 · see citing works
Self-citationDetermination of short-chain acyl-coenzyme A esters by high-performance liquid chromatography
Hosokawa, Y., Shimomura, Y., Harris, R. A., & Ozawa, T. (1986) · Analytical Biochemistry · doi:10.1016/0003-2697(86)90058-8 · Cited by 56 · see citing works
Flagged first, then by citations
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Sorted by citations
Newgard, C. B., An, J., Bain, J. R., Muehlbauer, M. J., Stevens, R. D., Lien, L. F., Haqq, A. M., Shah, S. H., Arlotto, M., Slentz, C. A., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.02.002 · Cited by 3,165 · see citing works
“Other laboratories have reported that elevations of long-chain acyl CoA levels in the hypothalamus, mediated by increased levels of malonyl CoA, may also constitute an important satiety signal (He et al., 2006; Pocai et al., 2006).”
BackgroundCentral nervous system control of food intake and body weight
Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S., & Schwartz, M. W. (2006) · Nature · doi:10.1038/nature05026 · Cited by 2,503 · see citing works
Steinberg, G. R., & Kemp, B. E. (2009) · Physiological Reviews · doi:10.1152/physrev.00011.2008 · Cited by 1,633 · see citing works
“Since the constitutively active AMPK fragment 1 (1-312) is not activated by the PT1 compound, it is proposed that PT1 acts by reversing the autoinhibition of the AIS (313-335).”
BackgroundInfluentialMolecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes
Muoio, D. M., & Newgard, C. B. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2327 · Cited by 1,177 · see citing works
Lipoprotein lipase: from gene to obesity
Wang, H., & Eckel, R. H. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90920.2008 · Cited by 862 · see citing works
“Pharmacological and molecular manipulations of hypothalamic nutrient sensing affect appetite, disrupt energy balance, and contribute in a substantial manner to body weight regulation (96).”
BackgroundHolland, W. L., Bikman, B. T., Wang, L.-P., Yuguang, G., Sargent, K. M., Bulchand, S., Knotts, T. A., Shui, G., Clegg, D. J., Wenk, M. R., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43378 · Cited by 705 · see citing works
“While aberrant accumulation of acyl-CoA and DAG has been implicated as a mediator of FFA-induced impairment of hypothalamic leptin and insulin action (23, 52), this is the first report that ceramide accumulates in the hypothalamus of rodents exposed to high-fat diets or saturated fat–enriched intravenous emulsions.”
BackgroundHypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance
López, M., Varela, L., Vazquez, M. J., Rodríguez‐Cuenca, S., González, C. R., Velagapudi, V., Morgan, D. A., Schoenmakers, E., Agassandian, K., Lage, R., et al. (2010) · Nature Medicine · doi:10.1038/nm.2207 · Cited by 682 · see citing works
“In support of this, recent evidence shows that although hypothalamic fatty acid metabolism has a key role in mediating adaptive feeding responses to fastin”
ResultThe Short-Chain Fatty Acid Acetate in Body Weight Control and Insulin Sensitivity
Hernández, M. A. G., Canfora, E. E., Jocken, J. W. E., & Blaak, E. E. (2019) · Nutrients · doi:10.3390/nu11081943 · Cited by 632 · see citing works
“the long-chain fatty acids to the mitochondrion [96,97].”
BackgroundFlanagan, J. L., Simmons, P. A., Vehige, J., Willcox, M. D., & Garrett, Q. (2010) · Nutrition & Metabolism · doi:10.1186/1743-7075-7-30 · Cited by 611 · see citing works
“There is some debate in the literature regarding whether satiety depends on the cytosolic concentration of long-chain fatty acids, with the suggestion that an increased concentration correlates with satiety and decreased feeding and body weight [77-80].”
BackgroundRegulation of lipid stores and metabolism by lipophagy
Liu, K., & Czaja, M. J. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2012.63 · Cited by 542 · see citing works
Hypothalamic Fatty Acid Metabolism Mediates the Orexigenic Action of Ghrelin
López, M., Lage, R., Saha, A. K., Pérez–Tilve, D., Vazquez, M. J., Varela, L., Sangiao‐Alvarellos, S., Tovar, S. A., Raghay, K., Rodríguez‐Cuenca, S., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.03.006 · Cited by 466 · see citing works
Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake
Kitamura, T., Feng, Y., Kitamura, Y., Chua, S. C., Xu, A. W., Barsh, G. S., Rossetti, L., & Accili, D. (2006) · Nature Medicine · doi:10.1038/nm1392 · Cited by 449 · see citing works
Self-citationGlucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony
Herman, M. A. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29027 · Cited by 349 · see citing works
Leptin and the Central Nervous System Control of Glucose Metabolism
Morton, G. J., & Schwartz, M. W. (2011) · Physiological Reviews · doi:10.1152/physrev.00007.2010 · Cited by 338 · see citing works
“, oleic acid, fatty acid synthase (FAS) inhibitor] in the CNS reduce food intake and HGP (99, 107, 133, 147), while conversely, pharmacological interventions that reduce hypothalamic malonyl CoA levels cause obesity and insulin resistance (79).”
BackgroundXue, B., & Kahn, B. B. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.113217 · Cited by 338 · see citing works
“In addition, adeno-associated virus-mediated gene transfer of malonyl-CoA decarboxylase, which is involved in the degradation of malonyl-CoA, into the medial basal hypothalamus of rats, results in increased food intake and progressive weight gain (He et al. 2006).”
BackgroundBrain Glucose Sensing, Counterregulation, and Energy Homeostasis
Marty, N., Dallaporta, M., & Thorens, B. (2007) · Physiology · doi:10.1152/physiol.00010.2007 · Cited by 330 · see citing works
“This suppresses food intake and reduces the expression of hypothalamic NPY and AgRP (46, 85).”
BackgroundInfluentialHypothalamic nutrient sensing in the control of energy homeostasis
Blouet, C., & Schwartz, G. J. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.12.024 · Cited by 321 · see citing works
“Acute inhibition or chronic deletion of hypothalamic CPT1 activity is sufficient to reduce food intake [139,192] and overexpression of mediobasal-hypothalamic malonyl-CoA decarboxylase (MCD), leading to a drop in the intracellular pool of long-chain fatty acyl-CoA, increases food intake and body weight gain [74].”
BackgroundInfluentialAMPK: Lessons from transgenic and knockout animals
Viollet, B. (2009) · Frontiers in bioscience · doi:10.2741/3229 · Cited by 314 · see citing works
Beta-glucans in higher fungi and their health effects
Rop, O., Mlček, J., & Juríková, T. (2009) · Nutrition Reviews · doi:10.1111/j.1753-4887.2009.00230.x · Cited by 280 · see citing works
Mechanisms Regulating Feed Intake, Energy Expenditure, and Body Weight in Poultry
Richards, M. P., & Proszkowiec‐Weglarz, M. (2007) · Poultry Science · doi:10.1093/ps/86.7.1478 · Cited by 269 · see citing works
“…levels of 2 key metabolites, malonyl-CoA, and long chain fatty acyl-CoA that, in turn, lead to changes in feed intake and energy expenditure by altering the expression of orexigenic and anorexigenic neuropeptides in melanocortin system neurons (Lane et al., 2005; Lam et al., 2005; He et al., 2006).”
BackgroundLipid Processing in the Brain: A Key Regulator of Systemic Metabolism
Bruce, K. D., Zsombok, A., & Eckel, R. H. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00060 · Cited by 264 · see citing works
“In addition, MBH expression depleted both malonyl-CoA and LCFA-CoA and was sufficient to induce hepatic insulin resistance in the presence of hyperlipidemia (75).”
BackgroundThe brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis
Wolfgang, M. J., Kurama, T., Dai, Y., Suwa, A., Asaumi, M., Matsumoto, S.-I., Cha, S. H., Shimokawa, T., & Lane, M. D. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602205103 · Cited by 250 · see citing works
Blouet, C., Jo, Y., Li, X., & Schwartz, G. J. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.1668-09.2009 · Cited by 240 · see citing works
“Indeed, leucine is solely ketogenic, and similarly to glucose and fatty acid, MBH leucine’s effects on energy balance could be a consequence of its intracellular metabolism (He et al., 2006; Wolfgang and Lane, 2008).”
BackgroundLeptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake
Gao, S., Kinzig, K. P., Aja, S., Scott, K. A., Keung, W., Kelly, S., Strynadka, K., Chohnan, S., Smith, W. W., Tamashiro, K. L. K., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708385104 · Cited by 215 · see citing works
Neurotrophic factor control of satiety and body weight
Xu, B., & Xie, X. (2016) · Nature reviews. Neuroscience · doi:10.1038/nrn.2016.24 · Cited by 203 · see citing works
“Gut hormone PYY(3-36) physiologically inhibits food intake.”
Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin
Liao, G., An, J. J., Gharami, K., Waterhouse, E. G., Vanevski, F., Jones, K. R., & Xu, B. (2012) · Nature Medicine · doi:10.1038/nm.2687 · Cited by 203 · see citing works
The Integrative Role of CNS Fuel-Sensing Mechanisms in Energy Balance and Glucose Regulation
Sandoval, D., Cota, D., & Seeley, R. J. (2008) · Annual Review of Physiology · doi:10.1146/annurev.physiol.70.120806.095256 · Cited by 178 · see citing works
Intranasal Insulin Suppresses Food Intake via Enhancement of Brain Energy Levels in Humans
Jauch‐Chara, K., Friedrich, A., Rezmer, M., Melchert, U. H., Scholand-Engler, H. G., Hallschmid, M., & Oltmanns, K. M. (2012) · Diabetes · doi:10.2337/db12-0025 · Cited by 164 · see citing works
Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis
Jordan, S. D., Könner, A. C., & Brüning, J. C. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0414-7 · Cited by 160 · see citing works
Carnitine, mitochondrial function and therapy
Zammit, V. A., Ramsay, R. R., Bonomini, M., & Arduini, A. (2009) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2009.04.024 · Cited by 149 · see citing works
Hypothalamic fatty acid metabolism: A housekeeping pathway that regulates food intake
López, M., Lelliott, C. J., & Vidal‐Puig, A. (2007) · BioEssays · doi:10.1002/bies.20539 · Cited by 144 · see citing works
“the medial basal hypothalamus of rats results in increased food intake and progressive weight gain.((88,89)) Finally, two”
BackgroundAhima, R. S., & Osei, S. Y. (2008) · Frontiers of hormone research · doi:10.1159/000115365 · Cited by 136 · see citing works
Ghrelin raises [Ca2+]i via AMPK in hypothalamic arcuate nucleus NPY neurons
Kohno, D., Sone, H., Minokoshi, Y., & Yada, T. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.11.166 · Cited by 131 · see citing works
Regulation of hypothalamic malonyl-CoA by central glucose and leptin
Wolfgang, M. J., Cha, S. H., Sidhaye, A., Chohnan, S., Cline, G., Shulman, G. I., & Lane, M. D. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709778104 · Cited by 127 · see citing works
Role for Mitochondrial Reactive Oxygen Species in Brain Lipid Sensing
Bénani, A., Troy, S., Carmona, M. C., Fioramonti, X., Lorsignol, A., Leloup, C., Casteilla, L., & Pénicaud, L. (2006) · Diabetes · doi:10.2337/db06-0440 · Cited by 132 · see citing works
“Sensing the abundance of the intracellular pool of malonyl-CoA is another way to monitor the fuel availability, and a persistent decrease in hypothalamic malonyl-CoA is sufficient to stimulate food intake and to induce obesity (15).”
BackgroundAppetite Regulation: An Overview
Dhillo, W. S. (2007) · Thyroid · doi:10.1089/thy.2007.0018 · Cited by 126 · see citing works
“Consistent with this, reduction of hypothalamic malonyl-CoA levels results in increased food intake and APPETITE REGULATION body weight (164,165).”
Neuronal regulation of homeostasis by nutrient sensing
Lam, T. K. T. (2010) · Nature Medicine · doi:10.1038/nm0410-392 · Cited by 125 · see citing works
Self-citationThe Role of CNS Fuel Sensing in Energy and Glucose Regulation
Cota, D., Proulx, K., & Seeley, R. J. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.03.049 · Cited by 117 · see citing works
The Role of Hypothalamic Malonyl-CoA in Energy Homeostasis
Wolfgang, M. J., & Lane, M. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.r600016200 · Cited by 114 · see citing works
CNS Regulation of Glucose Homeostasis
Lam, C., Chari, M., & Lam, T. K. T. (2009) · Physiology · doi:10.1152/physiol.00003.2009 · Cited by 110 · see citing works
“Additionally, overexpressing malonylCoA decarboxylase (MCD) in the hypothalamus of rodents negates the ability of circulating lipids to regulate glucose homeostasis (46).”
BackgroundSelf-citationHypothalamic leptin regulation of energy homeostasis and glucose metabolism
Morton, G. J. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.135590 · Cited by 112 · see citing works
“Conversely, hypothalamic reduction of LCFA-CoA levels by local infusion of adeno-associated virus expressing malonyl coenzyme A decarboxylase (MCD, an enzyme responsible for malonyl CoA degradation), causes obesity and insulin resistance in rats (He et al. 2006).”
BackgroundRole of AMP‐Activated Protein Kinase in the Control of Appetite
Kola, B. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2008.01745.x · Cited by 109 · see citing works
When do we eat? Ingestive behavior, survival, and reproductive success.
Schneider, J., Wise, J., Benton, N. A., Brozek, J., & Keen‐Rhinehart, E. (2013) · Hormones and Behavior · doi:10.1016/j.yhbeh.2013.07.005 · Cited by 107 · see citing works
“Food intake is increased by food restriction or deprivation, and by treatments that decrease levels of glucose oxidation, fatty acid oxidation, suppression of hepatic ATP levels, central activation of adenosine monophosphate-activated protein kinase (AMPK), enhanced expression of malonyl coenzyme A decarboxylase, and…”
BackgroundCeccarelli, S. M., Chomienne, O., Gubler, M., & Arduini, A. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm100809g · Cited by 108 · see citing works
Oleic Acid Directly Regulates POMC Neuron Excitability in the Hypothalamus
Jo, Y., Su, Y., Juárez, R. G., & Chua, S. C. (2009) · Journal of Neurophysiology · doi:10.1152/jn.91294.2008 · Cited by 104 · see citing works
Targeting the CNS to treat type 2 diabetes
Sandoval, D. A., Obici, S., & Seeley, R. J. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2874 · Cited by 100 · see citing works
Self-citationRole of hypothalamic AMP-kinase in food intake regulation
Minokoshi, Y., Shiuchi, T., Lee, S. P., Suzuki, A., & Okamoto, S. (2008) · Nutrition · doi:10.1016/j.nut.2008.06.002 · Cited by 94 · see citing works
Role of malonyl-CoA in heart disease and the hypothalamic control of obesity
Folmes, C. D. L., & LOPASCHUK, G. (2006) · Cardiovascular Research · doi:10.1016/j.cardiores.2006.10.008 · Cited by 95 · see citing works
“In support of this, increasing MCD expression in the arcuate nucleus (using adenoviral delivered MCD) results in an increase food intake and weight gain in mice and rats, and prevented leptin-induced inhibition of food intake [120].”
BackgroundMolecular and neural bases underlying roles of BDNF in the control of body weight
Vanevski, F., & Xu, B. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00037 · Cited by 95 · see citing works
“, 2001), and various metabolites such as glucose, fatty acids, and amino acids (Loftus et al., 2000; Cota et al., 2006; He et al., 2006; Pocai et al., 2006).”
BackgroundRegulation of food intake and energy expenditure by hypothalamic malonyl-CoA
Lane, M. D., Wolfgang, M. J., Cha, S.-H., & Dai, Y. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.123 · Cited by 92 · see citing works
Ghrelin and lipid metabolism: key partners in energy balance
Varela, L., Vazquez, M. J., Cordido, F., Nogueiras, R., Vidal‐Puig, A., Diéguez, C., & López, M. (2010) · Journal of Molecular Endocrinology · doi:10.1677/jme-10-0068 · Cited by 93 · see citing works
“This concept originates from earlier data showing that pharmacological inhibition and/or genetic ablation of hypothalamic CPT1 (Obici et al. 2003, Pocai et al. 2006, Wolfgang et al. 2006, Wolfgang & Lane 2008) or overexpression of MCD (He et al. 2006) induces the cytoplasmic accumulation of fatty acyl-CoA concentratio…”
InfluentialGao, S., Zhu, G., Gao, X., Wu, D., Carrasco, P., Casals, N., Hegardt, F. G., Moran, T. H., & Lopaschuk, G. D. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1103267108 · Cited by 91 · see citing works
“The up-regulation of AgRP level by MCD (9) was not affected by myriocin treatment (Fig.”
BackgroundInfluentialWolfgang, M. J., Cha, S. H., Millington, D. S., Cline, G. W., Shulman, G. I., Suwa, A., Asaumi, M., Kurama, T., Shimokawa, T., & Lane, M. D. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05255.x · Cited by 90 · see citing works
“This is surprising since it has been reported that fasting and refeeding can alter the long-chain acyl-CoA species in the hypothalamus of rats (He et al. 2006).”
BackgroundInfluentialCavaliere, G., Viggiano, E., Trinchese, G., Filippo, C. D., Messina, A., Monda, V., Valenzano, A. A., Cincione, R. I., Zammit, C., Cimmino, F., et al. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00818 · Cited by 90 · see citing works
“In addition, it has to be considered that activation of the hypothalamic AMPK is also responsible for alterations in fatty acid oxidation (He et al., 2006), leading to lipid overloaded hypertrophic adipocytes associated with inflammation and insulin resistance (Lionetti et al., 2009; Kim et al.,…”
BackgroundMinireview: The Brain as a Molecular Target for Diabetic Therapy
Prodi, E., & Obici, S. (2006) · Endocrinology · doi:10.1210/en.2006-0143 · Cited by 86 · see citing works
Self-citationPeripheral tissue–brain interactions in the regulation of food intake
López, M., Tovar, S. A., Vazquez, M. J., Williams, L. M., & Diéguez, C. (2007) · Proceedings of The Nutrition Society · doi:10.1017/s0029665107005368 · Cited by 87 · see citing works
“Impairment of hypothalamic lipid-sensing in rats induces obesity (He et al. 2006), as well alterations in plasma glucose (Pocai et al. 2006), indicating that this mechanism may be important in the physiological regulation of metabolism and body-weight homeostasis.”
BackgroundHypothalamic AMP-Activated Protein Kinase Regulates Glucose Production
Yang, C. S., Lam, C. K. L., Chari, M., Cheung, G. W. C., Kokorovic, A., Gao, S., Leclerc, I., Rutter, G. A., & Lam, T. K. T. (2010) · Diabetes · doi:10.2337/db10-0221 · Cited by 86 · see citing works
“Adenoviral MBH injections were performed as previously described (18), indicating that using this MBH adenoviral animal injection protocol, GFP is localized in the MBH and not other regions of the brain.”
BackgroundMethodInfluentialSelf-citationAcyl Coenzyme A Thioesterase 7 Regulates Neuronal Fatty Acid Metabolism To Prevent Neurotoxicity
Ellis, J. M., Wong, G. W., & Wolfgang, M. J. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01548-12 · Cited by 85 · see citing works
Chao, D. H. M., Argmann, C., van Eijk, M., Boot, R. G., Ottenhoff, R., van Roomen, C. P. A. A., Foppen, E., Siljee, J. E., Unmehopa, U. A., Kalsbeek, A., et al. (2016) · Scientific Reports · doi:10.1038/srep29094 · Cited by 84 · see citing works
Lipid Sensing and Insulin Resistance in the Brain
Yue, J. T. Y., & Lam, T. K. T. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.01.013 · Cited by 82 · see citing works
Self-citationPerspectives for feed-efficient animal production1
Niemann, H., Kuhla, B., & Flachowsky, G. (2011) · Journal of Animal Science · doi:10.2527/jas.2011-4235 · Cited by 82 · see citing works
“Few studies discuss the impact of the genotype on methane fermentation in the digestive tract of ruminants (Ferris et al., 1999; Hegarty, 2005).”
BackgroundBurmeister, M. A., Ferré, T., Ayala, J., Emily King, B. S., Holt, R. M., & Ayala, J. E. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00409.2011 · Cited by 81 · see citing works
“Increased hypothalamic malonylCoA has been associated with enhanced suppression of HGP (19, 32).”
BackgroundVillanueva, E. C., Münzberg, H., Cota, D., Leshan, R. L., Kopp, K., Ishida-Takahashi, R., Jones, J. C., Fingar, D. C., Seeley, R. J., & Myers, M. G. (2009) · Endocrinology · doi:10.1210/en.2009-0642 · Cited by 81 · see citing works
Cheng, L., Yu, Y., Szabo, A., Wu, Y., Wang, H., Camer, D., & Huang, X. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2014.12.011 · Cited by 80 · see citing works
“3 Introduction: The hypothalamus is capable of sensing nutritional status [1, 2], and as a result nutrients can influence brain function [3].”
BackgroundMalonyl CoenzymeA Decarboxylase Regulates Lipid and Glucose Metabolism in Human Skeletal Muscle
Bouzakri, K., Austin, R., Rune, A., Lassman, M. E., Garcia-Roves, P. M., Berger, J. P., Krook, A., Chibalin, A. V., Zhang, B. B., & Zierath, J. R. (2008) · Diabetes · doi:10.2337/db07-0583 · Cited by 77 · see citing works
“Conversely, hypothalamic overexpression of MCD (21), inhibition of ACC (11), or activation of AMPK (43) to decrease the level of malonyl-CoA stimulates food intake.”
BackgroundGlucose sensing and the pathogenesis of obesity and type 2 diabetes
Thorens, B. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.208 · Cited by 78 · see citing works
Brain glucose sensing: a subtle mechanism
Pénicaud, L., Leloup, C., Fioramonti, X., Lorsignol, A., & Bénani, A. (2006) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/01.mco.0000232908.84483.e0 · Cited by 75 · see citing works
Ziko, I., Luca, S. N. D., Dinan, T., Barwood, J. M., Sominsky, L., Cai, G., Kenny, R., Stokes, L., Jenkins, T. A., & Spencer, S. J. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.06.014 · Cited by 73 · see citing works
CNS-targets in control of energy and glucose homeostasis
Kleinridders, A., Könner, A. C., & Brüning, J. C. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.10.006 · Cited by 72 · see citing works
Effect of glucose and fructose on food intake via malonyl-CoA signaling in the brain
Lane, M. D., & Cha, S. H. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.02.145 · Cited by 71 · see citing works
Hypothalamic Leucine Metabolism Regulates Liver Glucose Production
Su, Y., Lam, T. K. T., He, W., Pocai, A., Bryan, J., Aguilar‐Bryan, L., & Juárez, R. G. (2011) · Diabetes · doi:10.2337/db11-0857 · Cited by 70 · see citing works
“No significant effect of MCD overexpression per se was observed (29) (Table 1).”
BackgroundMethodInfluentialSelf-citationHypothalamic lipotoxicity and the metabolic syndrome
de Morentin, P. B. M., Varela, L., Fernø, J., Nogueiras, R., Diéguez, C., & López, M. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.09.016 · Cited by 70 · see citing works
“whole body level [5,6,15,17–19,40,45,48,49,53,55,57,58,60,61,75,77– 79,86,90,95,97,106,121,124,125,129,130,143,144].”
MethodThe ghrelin/GOAT/GHS-R system and energy metabolism
Lim, C. T., Kola, B., & Korbonits, M. (2011) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-011-9169-1 · Cited by 69 · see citing works
“Both these events lead to the activation of carnitine palmitoyl transferase 1 (CPT1) and the degradation of malonyl-CoA in the medial basal hypothalamus [85–87].”
BackgroundGao, X., Li, K., Hui, X., Kong, X., Sweeney, G., Wang, Y., Xu, A., Teng, M., Liu, P., & Wu, D. (2011) · Biochemical Journal · doi:10.1042/bj20101680 · Cited by 68 · see citing works
Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite
Lopaschuk, G. D., Ussher, J. R., & Jaswal, J. S. (2010) · Pharmacological Reviews · doi:10.1124/pr.109.002428 · Cited by 68 · see citing works
“Likewise, mice with STAT3 signaling abrogated via mutation of tyrosine residue 1178 to alanine in the leptin receptor have a phenotype mimicking the hyperphagia and obesity observed in leptin receptor-deficient db/db mice (Bates et al., 2003).”
BackgroundInfluentialSphingolipid Metabolism and Obesity-Induced Inflammation
Kang, S. C., Kim, B.-R., Lee, S., & Park, T. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00067 · Cited by 68 · see citing works
“Recent reports clearly show that FA in hypothalamus plays an important role in energy balance (Obici et al., 2003; He et al., 2006; Lopez et al., 2006).”
BackgroundCha, S.-H., Rodgers, J. T., Puigserver, P., Chohnan, S., & Lane, M. D. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607334103 · Cited by 65 · see citing works
Many mouths to feed: the control of food intake during lactation.
Woodside, B., Budin, R., Wellman, M. K., & Abizaid, A. (2012) · Frontiers in neuroendocrinology (Print) · doi:10.1016/j.yfrne.2012.09.002 · Cited by 54 · see citing works
“…receptors in this area alter the stimulation thresholds of these neurons either via changes in their membrane sensitivity to classical neurotransmitters, or by altering sensitivity to nutritional signals such as glucose or free fatty acids (Cowley et al., 2001; He et al., 2006; Liu et al., 2011).”
BackgroundBorer, K. T., Wuorinen, E. C., Ku, K. P., & Burant, C. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-2495 · Cited by 66 · see citing works
“This would suggest operation of an all-or-none meal initiation signal that responds to the absence of food in the gastrointestinal tract, to brain detection of energy deficit (7, 8), and probably also to circadian timing.”
BackgroundMediobasal Hypothalamic SIRT1 Is Essential for Resveratrol’s Effects on Insulin Action in Rats
Knight, C. M., Juárez, R. G., Lam, T. K. T., Arrieta‐Cruz, I., Huang, L., Schwartz, G. J., Barzilai, N., & Rossetti, L. (2011) · Diabetes · doi:10.2337/db10-0987 · Cited by 67 · see citing works
“Gene expression of proopiomelanocortin (POMC) and agouti-related peptide (AgRP) was determined by RT-PCR as previously described (35).”
MethodSelf-citationDiet, obesity and diabetes: a current update
Walker, C. G., Zariwala, M. G., Holness, M. J., & Sugden, M. C. (2006) · Clinical Science · doi:10.1042/cs20060150 · Cited by 62 · see citing works
Taïb, B., Bouyakdan, K., Hryhorczuk, C., Rodaros, D., Fulton, S., & Alquier, T. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.506238 · Cited by 65 · see citing works
“In addition, they suggest that the previously described effect of MCD overexpression in the MBH, the malonyl-CoA-degrading enzyme, leading to increased food intake and adiposity (17, 18) may involve modulation ofmalonyl-CoA andLCFA-CoAoxidation in astrocytes and/or neurons.”
BackgroundHypothalamic malonyl-CoA and CPT1c in the treatment of obesity
Wolfgang, M. J., & Lane, M. D. (2010) · FEBS Journal · doi:10.1111/j.1742-4658.2010.07978.x · Cited by 64 · see citing works
Gao, X., Chen, W., Kong, X., Xu, A., Wang, Z. G., Sweeney, G., & Wu, D. (2009) · Diabetologia · doi:10.1007/s00125-009-1284-0 · Cited by 64 · see citing works
“We also detected decreased fatty oxidation and oxidative genes expression in liver and skeletal muscle and so it appears that the opposing responses of oxidative enzymatic activity in central and peripheral systems ultimately contribute to impaired glucose tolerance [17, 37, 42].”
BackgroundLam, C., Chari, M., Rutter, G. A., & Lam, T. K. T. (2010) · Diabetes · doi:10.2337/db10-0994 · Cited by 63 · see citing works
“Immediately poststereotaxic surgery, rats were injected with 3 l adenovirus per side of cannulae into the MBH and/or DVC as previously described (12,18,20).”
MethodSelf-citationA Balance of Lipid-Sensing Mechanisms in the Brain and Liver
Caspi, L., Wang, P. Y. T., & Lam, T. K. T. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.07.005 · Cited by 58 · see citing works
Self-citationEvidence for Central Regulation of Glucose Metabolism
Carey, M., Kehlenbrink, S., & Hawkins, M. A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.r113.506782 · Cited by 57 · see citing works
“Malonyl-CoA, the intermediate molecule in fatty acid biosynthesis, is a hypothalamic indicator of whole body nutritional status inmice (54) and rats (55).”
BackgroundHypothalamic Protein Kinase C Regulates Glucose Production
Ross, R., Wang, P. Y. T., Chari, M., Lam, C., Caspi, L., Ono, H., Muse, E. D., Li, X., Juárez, R. G., Light, P. E., et al. (2008) · Diabetes · doi:10.2337/db08-0206 · Cited by 57 · see citing works
Self-citationAja, S. M., Landree, L. E., Kleman, A. M., Medghalchi, S. M., Vadlamudi, A., McFadden, J. M., Aplasca, A., Hyun, J., Plummer, E. R., Daniels, K., et al. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00862.2006 · Cited by 58 · see citing works
“These data do not support the current long-chain fatty acid-sensing hypothesis for regulating organism energy balance (16, 24, 35, 41).”
BackgroundResultNeuronal Sirt1 Deficiency Increases Insulin Sensitivity in Both Brain and Peripheral Tissues
Lu, M. M., Sarruf, D. A., Li, P., Osborn, O., Sánchez-Alavez, M., Talukdar, S., Chen, A., Bandyopadhyay, G. K., Xu, J., Morinaga, H., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.443606 · Cited by 57 · see citing works
“Similarly activation of malonyl CoA decarboxylase in liver leads to fatty acid oxidation and reduced lipid content (33), while activation of this enzyme in themediobasal hypothalamus induces hyperphagia and obesity (34).”
BackgroundDuca, F. A., Bauer, P. V., Hamr, S. C., & Lam, T. K. T. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.07.003 · Cited by 56 · see citing works
Self-citationProulx, K., Cota, D., Woods, S. C., & Seeley, R. J. (2008) · Diabetes · doi:10.2337/db07-1690 · Cited by 55 · see citing works
“Acetyl-CoA carboxylase (ACC) and FAS are expressed in the hypothalamus (7), where malonyl-CoA (11) and LCFACoA levels (8) decrease during fasting and increase after refeeding.”
BackgroundHypothalamic malonyl-CoA and the control of food intake
Gao, S., Moran, T. H., Lopaschuk, G. D., & Butler, A. A. (2013) · Physiology & Behavior · doi:10.1016/j.physbeh.2013.07.014 · Cited by 52 · see citing works
“Conversely, decreases in malonyl-CoA levels (when food intake is augmented) are associated with upregulations of NPY and AgRP [41].”
InfluentialThe return of malonyl-CoA to the brain: Cognition and other stories
Fadó, R., Rodríguez‐Rodríguez, R., & Casals, N. (2020) · Progress in Lipid Research · doi:10.1016/j.plipres.2020.101071 · Cited by 49 · see citing works
Poplawski, M. M., Mastaitis, J. W., Yang, X.-J., & Mobbs, C. V. (2010) · Endocrinology · doi:10.1210/en.2010-0702 · Cited by 49 · see citing works
Localization and effect of ectopic expression of CPT1c in CNS feeding centers
Dai, Y., Wolfgang, M. J., Cha, S. H., & Lane, M. D. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.05.161 · Cited by 48 · see citing works
Physiological and Epigenetic Features of Yoyo Dieting and Weight Control
Contreras, R. E., Schriever, S. C., & Pfluger, P. T. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.01015 · Cited by 52 · see citing works
Shedding light on the intricate puzzle of ghrelin's effects on appetite regulation
Kola, B., & Korbonits, M. (2009) · Journal of Endocrinology · doi:10.1677/joe-09-0056 · Cited by 48 · see citing works
“In support of this mechanism, degradation of malonyl-CoA in the medial basal hypothalamus of rats results in increased food intake and progressive weight gain (He et al. 2006), while inhibition of CPT1 in the hypothalamus suppresses food intake (Obici et al. 2003, Pocai et al. 2006; Fig.”
BackgroundGhrelin-mediated appetite regulation in the central nervous system
Kirsz, K., & Zieba, D. A. (2011) · Peptides · doi:10.1016/j.peptides.2011.04.010 · Cited by 47 · see citing works
Towards a ‘systems’-level understanding of the nervous system and its disorders
Qureshi, I., & Mehler, M. F. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2013.07.003 · Cited by 46 · see citing works
- Authors
- He, W., Lam, T. K. T., Obici, S., & Rossetti, L.
- Affiliations
- Albert Einstein College of Medicine (US)
- Corresponding author
- Rossetti, Luciano
- Venue
- Nature Neuroscience
- Published
- 2006-01-15
- Volume
- 9
- Issue
- 2
- Pages
- 227-233
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2076637814
- Cited by
- 233
- References
- 31
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 7 · 2016: 7 · 2015: 7 · 2014: 8 · 2013: 18 · 2012: 16
- FWCI
- 12.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Skirball Foundation
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- obesity, malonyl-CoA decarboxylase, mediobasal hypothalamus, energy homeostasis, fatty acyl-CoA, dietary intake, leptin, insulin, malonyl-CoA, AAV gene delivery, lipid availability
- MeSH terms
- Animals, Energy Intake, Carboxy-Lyases, Eating, Fluorescent Antibody Technique, Hypothalamus, Male, Obesity, Blotting, Western, Glucose Clamp Technique, Rats, Sprague-Dawley, Lipid Metabolism, Rats
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