Pyruvate and Satiety: Can We Fool the Brain?
http://www.100md.com
内分泌学杂志 2005年第1期
Department of Experimental and Environmental Medicine and Biotechnology, University of Milano-Bicocca, 20052 Monza, Italy
Address all correspondence and requests for reprints to: Vittorio Locatelli, Department of Experimental and Environmental Medicine and Biotechnology, University Milano-Bicocca, via Cadore 48, 20052 Monza, Italy. E-mail: vittorio.locatelli@unimib.it.
Introduction
In the last few years, our understanding of the physiological systems that regulate food intake and body weight has increased enormously. A growing number of factors and signaling molecules involved in food intake and its hormonal regulation indicate that this behavior is coordinated by highly complex processes (1, 2, 3, 4). Orexigenic and satiety systems, although finely balanced, seem more effective in protecting against starvation than overfeeding, thus predisposing us to obesity (5). As the obesity epidemic spreads, concerns are growing about its significant health and economic consequences (6), emphasizing the need for a more complete understanding.
The "Fuel Gauge" for Nutrients
Hypothalamic neurons can directly sense circulating nutrients (7, 8); however, the exact molecular mechanisms by which the sensing neurons recognize energy need and translate it into signals for feeding behavior remain largely unknown. The 5'-AMP-activated protein kinase (AMPK) has been proposed to serve as a fuel sensor in the hypothalamus (9, 10, 11, 12), an evolutionarily conserved function that is important even in yeast (13). Activation of AMPK is prompted by an increase in the AMP:ATP ratio or by other upstream kinases (14). Whether AMPK activation is the real fuel gauge must still be ascertained, but many have demonstrated that AMPK activation is correlated to glucose levels (9, 10, 15). In this issue, Lee et al. (16) have used neuroblastoma cell lines to study correlations between glucose levels, AMPK activation, and agouti-related protein (AgRP) expression. AgRP is a well-known, potent stimulator of feeding behavior (2, 3). Degrees of AMPK phosphorylation were linearly and inversely correlated with increasing glucose concentrations at physiological levels. Thus, small modifications in glucose levels can be sensed by neurons to generate hunger or satiety signals. Other research is needed to clarify the exact molecular steps linking glucose to AMPK phosphorylation and AMPK phosphorylation to AgRP synthesis and release.
The Need for a Model
Lee et al. used two neuroblastoma cell lines to directly test the effect of glucose on AgRP expression, avoiding the disadvantages of indirect, confusing effects brought by interactions of cells with other neuronal systems and changes in blood hormones or substrates. In this simplified system, glucoprivic conditions elicited low cellular ATP concentration and increased AMPK phosphorylation, which in turn stimulated AgRP expression (Fig. 1A ). Lee et al. also observed that inhibition of glycolysis by 2-deoxy-D-glucose, a nonmetabolizable glucose analog that inhibits glucose utilization, increased AgRP expression in the neuronal cell lines (Fig. 1B ). Therefore, they propose that glucose metabolites in the glycolysis pathway may be the effector molecules primarily responsible for regulation of AMPK activation and AgRP expression. Because pyruvate effectively suppressed the increase in AgRP expression induced by 2-deoxy-D-glucose in these cells, the authors suggest that downstream metabolites of the glycolysis pathway beyond pyruvate might be responsible for regulation of AgRP expression (Fig. 1B ). Moreover, overexpression of a dominant-inhibitory mutant of AMPK significantly decreased low-glucose-induced AgRP expression, thus confirming the role of cerebral AMPK in the central effects of glucose.
FIG. 1. Cartoon with a schematic representation of the purported mechanism used by neuronal cells to convert nutrient status into feeding signals. A, In the fed status, high glucose levels are converted into pyruvate, which contribute to increase ATP levels. The AMP:ATP ratio is low, AMPK is scarcely activated, and little expression of AgRP/neuropeptide Y (NPY) occurs. Conversely, when glucose is low, the AMPK is largely activated and AgRP/NPY are efficiently transcribed. B, In the high glucose status, 2-deoxy-D-glucose supplementation inhibits pyruvate formation, shifting the scheme to the low glucose situation; this status may be effectively rescued by pyruvate, which restores AMPK phosphorylation and promotes AgRP/NPY expression.
Not Just Glucose
Neurons rely mainly on glucose for their energy supply but still retain the ability to respond to changing levels of fatty acids. Central administration of oleic acid inhibits food intake and glucose production (7). Precursors in fatty acid biosynthesis, such as the intermediate product of the synthesis of fatty acids, malonyl-coenzyme A (CoA), have also been proposed as possible mediators of the hypothalamic signaling pathway that monitors energy status. Phosphorylated AMPK activates catabolic pathways that generate ATP, while inhibiting anabolic, ATP-consuming pathways such as those implicated in fatty acid synthesis. Although interesting results implicate malonyl-CoA as a mediator linking the synthesis of hypothalamic fatty acid to the inhibition of food intake, they do not define the signaling mechanism beyond malonyl-CoA in the pathways regulating the expression of hypothalamic orexigenic (neuropeptide Y and AgRP) and anorexigenic (proopiomelanocortin) neuropeptides mRNAs (17).
Many studies suggest that modulation of intraneuronal ATP levels triggers a cascade of events via AMPK that modulate feeding behavior to restore energy status of cells (12, 16, 18). Therefore, the common pathway for sensing glucose, fatty acids, and other nutrient levels might be represented by the energy status of the cell. These key findings should provide novel intervention opportunities for manipulation of feeding behavior.
The work by Lee et al. (16) presented in this issue is another brick in support of the general hypothesis that energy status of the nutrient-sensing cells of the brain is the major switch for the control of neuropeptide expression and feeding behavior (19). Detailed understanding the mechanisms of nutrient sensing could lead to new approaches to prevent or reverse obesity.
References
Sahu A 2004 Minireview: a hypothalamic role in energy balance with special emphasis on leptin. Endocrinology 145:2613–2620
Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS 1999 Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 20:68–100
Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG 2000 Central nervous system control of food intake. Nature 404:661–671
Wynne K, Stanley S, Bloom S 2004 The gut and regulation of body weight. J Clin Endocrinol Metab 89:2576–2582
Schwartz MW, Woods SC, Seeley RJ, Barsh GS, Baskin DG, Leibel RL 2003 Is the energy homeostasis system inherently biased toward weight gain? Diabetes 52:232–238
Stein CJ, Colditz GA 2004 The epidemic of obesity. J Clin Endocrinol Metab 89:2522–2525
Obici S, Rossetti L 2003 Minireview: nutrient sensing and the regulation of insulin action and energy balance. Endocrinology 144:5172–5178
Morgan K, Obici S, Rossetti L 2004 Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J Biol Chem 23:31139–31148
Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB 2004 AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428:569–574
Kim MS, Park JY, Namkoong C, Jang PG, Ryu JW, Song HS, Yun JY, Namgoong IS, Ha J, Park IS, Lee IK, Viollet B, Youn JH, Lee HK, Lee KU 2004 Anti-obesity effects of -lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med 10:727–733
Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ 2004 AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 279:12005–12008
Kim EK, Miller I, Aja S, Landree LE, Pinn M, McFadden J, Kuhajda FP, Moran TH, Ronnett GV 2004 C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem 279:19970–19976
Hardie DG 2003 Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144:5179–5183
Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG 2003 Complexes between the LKB1 tumor suppressor, STRAD- /ß and MO25 /ß are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2:28
McCrimmon RJ, Fan X, Ding Y, Zhu W, Jacob RJ, Sherwin RS 2004 Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes 53:1953–1958
Lee K, Li B, Xi X, Suh Y, Martin RJ 2005 Role of neuronal energy status in the regulation of adenosine 5'-monophosphate-activated protein kinase, orexigenic neuropeptides expression, and feeding behavior. Endocrinology 146:3–10
Hu Z, Cha SH, Chohnan S, Lane MD 2003 Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proc Natl Acad Sci USA 100:12624–12629
Landree LE, Hanlon AL, Strong DW, Rumbaugh G, Miller IM, Thupari JN, Connolly EC, Huganir RL, Richardson C, Witters LA, Kuhajda FP, Ronnett GV 2004 C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism. J Biol Chem 279:3817–3827
Peters A, Schweiger U, Pellerin L, Hubold C, Oltmann KM, Conrad M, Schultes B, Born J, Fehm HL 2004 The selfish brain: competition for energy resources. Neurosci Biobehav Rev 28:143–180(Vittorio Locatelli and An)
Address all correspondence and requests for reprints to: Vittorio Locatelli, Department of Experimental and Environmental Medicine and Biotechnology, University Milano-Bicocca, via Cadore 48, 20052 Monza, Italy. E-mail: vittorio.locatelli@unimib.it.
Introduction
In the last few years, our understanding of the physiological systems that regulate food intake and body weight has increased enormously. A growing number of factors and signaling molecules involved in food intake and its hormonal regulation indicate that this behavior is coordinated by highly complex processes (1, 2, 3, 4). Orexigenic and satiety systems, although finely balanced, seem more effective in protecting against starvation than overfeeding, thus predisposing us to obesity (5). As the obesity epidemic spreads, concerns are growing about its significant health and economic consequences (6), emphasizing the need for a more complete understanding.
The "Fuel Gauge" for Nutrients
Hypothalamic neurons can directly sense circulating nutrients (7, 8); however, the exact molecular mechanisms by which the sensing neurons recognize energy need and translate it into signals for feeding behavior remain largely unknown. The 5'-AMP-activated protein kinase (AMPK) has been proposed to serve as a fuel sensor in the hypothalamus (9, 10, 11, 12), an evolutionarily conserved function that is important even in yeast (13). Activation of AMPK is prompted by an increase in the AMP:ATP ratio or by other upstream kinases (14). Whether AMPK activation is the real fuel gauge must still be ascertained, but many have demonstrated that AMPK activation is correlated to glucose levels (9, 10, 15). In this issue, Lee et al. (16) have used neuroblastoma cell lines to study correlations between glucose levels, AMPK activation, and agouti-related protein (AgRP) expression. AgRP is a well-known, potent stimulator of feeding behavior (2, 3). Degrees of AMPK phosphorylation were linearly and inversely correlated with increasing glucose concentrations at physiological levels. Thus, small modifications in glucose levels can be sensed by neurons to generate hunger or satiety signals. Other research is needed to clarify the exact molecular steps linking glucose to AMPK phosphorylation and AMPK phosphorylation to AgRP synthesis and release.
The Need for a Model
Lee et al. used two neuroblastoma cell lines to directly test the effect of glucose on AgRP expression, avoiding the disadvantages of indirect, confusing effects brought by interactions of cells with other neuronal systems and changes in blood hormones or substrates. In this simplified system, glucoprivic conditions elicited low cellular ATP concentration and increased AMPK phosphorylation, which in turn stimulated AgRP expression (Fig. 1A ). Lee et al. also observed that inhibition of glycolysis by 2-deoxy-D-glucose, a nonmetabolizable glucose analog that inhibits glucose utilization, increased AgRP expression in the neuronal cell lines (Fig. 1B ). Therefore, they propose that glucose metabolites in the glycolysis pathway may be the effector molecules primarily responsible for regulation of AMPK activation and AgRP expression. Because pyruvate effectively suppressed the increase in AgRP expression induced by 2-deoxy-D-glucose in these cells, the authors suggest that downstream metabolites of the glycolysis pathway beyond pyruvate might be responsible for regulation of AgRP expression (Fig. 1B ). Moreover, overexpression of a dominant-inhibitory mutant of AMPK significantly decreased low-glucose-induced AgRP expression, thus confirming the role of cerebral AMPK in the central effects of glucose.
FIG. 1. Cartoon with a schematic representation of the purported mechanism used by neuronal cells to convert nutrient status into feeding signals. A, In the fed status, high glucose levels are converted into pyruvate, which contribute to increase ATP levels. The AMP:ATP ratio is low, AMPK is scarcely activated, and little expression of AgRP/neuropeptide Y (NPY) occurs. Conversely, when glucose is low, the AMPK is largely activated and AgRP/NPY are efficiently transcribed. B, In the high glucose status, 2-deoxy-D-glucose supplementation inhibits pyruvate formation, shifting the scheme to the low glucose situation; this status may be effectively rescued by pyruvate, which restores AMPK phosphorylation and promotes AgRP/NPY expression.
Not Just Glucose
Neurons rely mainly on glucose for their energy supply but still retain the ability to respond to changing levels of fatty acids. Central administration of oleic acid inhibits food intake and glucose production (7). Precursors in fatty acid biosynthesis, such as the intermediate product of the synthesis of fatty acids, malonyl-coenzyme A (CoA), have also been proposed as possible mediators of the hypothalamic signaling pathway that monitors energy status. Phosphorylated AMPK activates catabolic pathways that generate ATP, while inhibiting anabolic, ATP-consuming pathways such as those implicated in fatty acid synthesis. Although interesting results implicate malonyl-CoA as a mediator linking the synthesis of hypothalamic fatty acid to the inhibition of food intake, they do not define the signaling mechanism beyond malonyl-CoA in the pathways regulating the expression of hypothalamic orexigenic (neuropeptide Y and AgRP) and anorexigenic (proopiomelanocortin) neuropeptides mRNAs (17).
Many studies suggest that modulation of intraneuronal ATP levels triggers a cascade of events via AMPK that modulate feeding behavior to restore energy status of cells (12, 16, 18). Therefore, the common pathway for sensing glucose, fatty acids, and other nutrient levels might be represented by the energy status of the cell. These key findings should provide novel intervention opportunities for manipulation of feeding behavior.
The work by Lee et al. (16) presented in this issue is another brick in support of the general hypothesis that energy status of the nutrient-sensing cells of the brain is the major switch for the control of neuropeptide expression and feeding behavior (19). Detailed understanding the mechanisms of nutrient sensing could lead to new approaches to prevent or reverse obesity.
References
Sahu A 2004 Minireview: a hypothalamic role in energy balance with special emphasis on leptin. Endocrinology 145:2613–2620
Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS 1999 Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 20:68–100
Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG 2000 Central nervous system control of food intake. Nature 404:661–671
Wynne K, Stanley S, Bloom S 2004 The gut and regulation of body weight. J Clin Endocrinol Metab 89:2576–2582
Schwartz MW, Woods SC, Seeley RJ, Barsh GS, Baskin DG, Leibel RL 2003 Is the energy homeostasis system inherently biased toward weight gain? Diabetes 52:232–238
Stein CJ, Colditz GA 2004 The epidemic of obesity. J Clin Endocrinol Metab 89:2522–2525
Obici S, Rossetti L 2003 Minireview: nutrient sensing and the regulation of insulin action and energy balance. Endocrinology 144:5172–5178
Morgan K, Obici S, Rossetti L 2004 Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J Biol Chem 23:31139–31148
Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB 2004 AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428:569–574
Kim MS, Park JY, Namkoong C, Jang PG, Ryu JW, Song HS, Yun JY, Namgoong IS, Ha J, Park IS, Lee IK, Viollet B, Youn JH, Lee HK, Lee KU 2004 Anti-obesity effects of -lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med 10:727–733
Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ 2004 AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 279:12005–12008
Kim EK, Miller I, Aja S, Landree LE, Pinn M, McFadden J, Kuhajda FP, Moran TH, Ronnett GV 2004 C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem 279:19970–19976
Hardie DG 2003 Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144:5179–5183
Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG 2003 Complexes between the LKB1 tumor suppressor, STRAD- /ß and MO25 /ß are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2:28
McCrimmon RJ, Fan X, Ding Y, Zhu W, Jacob RJ, Sherwin RS 2004 Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes 53:1953–1958
Lee K, Li B, Xi X, Suh Y, Martin RJ 2005 Role of neuronal energy status in the regulation of adenosine 5'-monophosphate-activated protein kinase, orexigenic neuropeptides expression, and feeding behavior. Endocrinology 146:3–10
Hu Z, Cha SH, Chohnan S, Lane MD 2003 Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proc Natl Acad Sci USA 100:12624–12629
Landree LE, Hanlon AL, Strong DW, Rumbaugh G, Miller IM, Thupari JN, Connolly EC, Huganir RL, Richardson C, Witters LA, Kuhajda FP, Ronnett GV 2004 C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism. J Biol Chem 279:3817–3827
Peters A, Schweiger U, Pellerin L, Hubold C, Oltmann KM, Conrad M, Schultes B, Born J, Fehm HL 2004 The selfish brain: competition for energy resources. Neurosci Biobehav Rev 28:143–180(Vittorio Locatelli and An)