- Email: [email protected]
Running on Empty: Leptin Signaling in VTA Regulates Reward from Physical Activity
Cell Metabolism
Previews Running on Empty: Leptin Signaling in VTA Regulates Reward from Physical Activity Zuxin Chen1 and Paul J. Kenny1,* 1Department of Pharmacology & Systems Therapeutics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2015.09.021
Hunger increases physical activity and stamina to support food-directed foraging behaviors, but underlying mechanisms are unclear. In this issue, Fernandes et al. (2015) show that disruption of leptin-regulated STAT3 signaling in midbrain dopamine neurons increases the rewarding effects of running in mice, which could explain the ‘‘high’’ experienced by endurance runners. It might be expected that hungry animals reduce their energy expenditure to conserve already depleted energy reserves. However, humans and rodents often increase physical activity when hungry. Hunger also increases sensitivity of brain reward systems (Carr, 1996). Conceptually, this increase in reward function serves to enhance the motivational value of physical activity, which in turn facilitates foraging behaviors, and increases pleasure derived from successful foraging, a powerful combination in the context of food seeking. Currently, it is unclear how energy balance is coupled to physical activity. Also unclear is whether the same brain systems regulate the enhanced rewarding value of physical activity and food during hunger states. Circulating leptin levels are usually reduced in hungry animals, which promotes physical activity when food is limited. Infusion of leptin into the ventral tegmental area (VTA), a brain site in which dopamine-containing neurons play a key role in regulating motivated behaviors, suppresses hyperactivity during starvation (Verhagen et al., 2011). This suggests that leptin signaling in the VTA may link energy status to physical activity. In this issue, Fernandes et al. (2015) provide compelling evidence supporting this hypothesis. Leptin acts in neurons primarily through STAT3 (signal transducer and activator of transcription 3) (Bates et al., 2003). To investigate the role for dopamine neurons in regulating the behavioral actions of leptin, Fernandes et al. (2015) conditionally deleted STAT3 in these neurons. This was accomplished by crossing mice
with loxP sites flanking exon 22 of the STAT3 gene with those expressing Cre recombinase under the control of the dopamine transporter gene (DAT), thereby generating STAT3DAT knockout (KO) mice. Although daily food intake, heat dissipation, and respiratory exchange were not impacted, the body weight of STAT3DAT KO mice was significantly lower than control mice. This effect was explained by a dramatic increase in their physical activity. When a running wheel was made available, the KO mice ran almost twice as much as control mice (11 versus 6 km day 1). This increase in physical activity is unlikely to be explained by alterations in anxiety-related behaviors, as KO and control mice demonstrated similar behavior in an elevated-plus maze and open field. Importantly, virus-mediated re-expression of STAT3 selectively in VTA dopamine neurons normalized running behavior in the conditional KO mice, confirming their role in the observed effects. The findings suggest that leptin, acting through STAT3 in VTA dopamine neurons, controls levels of physical activity in mice. Next, the authors investigated the mechanisms by which STAT3 controls running. Using a place conditioning procedure, they found that STAT3DAT KO mice spent far more time than controls exploring an environment in which a running wheel was previously available. This suggests that the rewarding properties of running were greatly potentiated in the KO mice. Interestingly, STAT3DAT KO mice did not demonstrate any evidence for altered sensitivity to rewarding properties of palatable food. Anorectic responses to leptin were also unaltered in the KO mice. This
540 Cell Metabolism 22, October 6, 2015 ª2015 Elsevier Inc.
provides strong evidence that STAT3 signaling in VTA inhibits the rewarding properties of physical activity, but not food, and raises the interesting issue of where in the brain leptin acts to regulate food reward. The lateral hypothalamus (LH) is considered a core component of the brain reward system, and its sensitivity to reward is influenced by hunger in a leptin-dependent manner (Fulton et al., 2000). Moreover, leptin was recently shown to activate STAT3 signaling in a population of inhibitory neurons in LH, which suppressed food intake in mice (Leinninger et al., 2009). Interestingly, these leptinresponsive LH neurons directly innervate VTA dopamine neurons (Leinninger et al., 2009). Hence, leptin likely acts in the VTA and LH to control the rewarding effects of physical activity and food, respectively, with these sites sharing close leptin-regulated functional interactions. Finally, the authors investigated mechanisms by which STAT3 signaling in dopamine neurons controls running. Psychomotor stimulants such as amphetamine and cocaine increase locomotor activity by stimulating dopamine transmission in nucleus accumbens (NAc). Dopamine signaling in NAc is hypothesized to regulate the rewarding properties of wheel running (Roberts et al., 2012). It is therefore surprising that the STAT3DAT KO mice demonstrated a profound deficit in evoked dopamine release into the core of the NAc. The KO mice also demonstrated diminished sensitivity to the locomotor stimulant effects of amphetamine and a dopamine D1 receptor agonist. Considering the well-established role for dopamine in regulating motor behavior, these findings appear
Cell Metabolism
Previews counterintuitive. Nevertheless, they are consistent with recent data showing that running distance is inversely correlated with evoked dopamine release in NAc in rats (Tarr et al., 2004) and that hyperlocomotion can occur independent of dopamine transmission in NAc (Chartoff et al., 2005). How does ablation of STAT3 signaling in VTA dopamine neurons, concomitant with reductions in evoked dopamine release in NAc, precipitate such dramatic increases in the rewarding properties of running? The authors offered a tantalizing piece of preliminary evidence suggesting that the STAT3DAT KO mice have reduced pre-prodynorphin mRNA levels in the VTA. Pre-prodynorphin is produced by the so called ‘‘direct pathway’’ medium spiny neurons in striatum, which provide feedback innervation to the midbrain dopamine system. Moreover, it is known that dynorphin, the mature opioid peptide encoded by this precursor gene, stimulates k opioid receptors (KORs) to inhibit locomotor activity. Perhaps reductions in KOR signaling in the VTA, driven by decreases in dopa-
mine release in NAc, stimulates running behavior in a dopamine-independent manner in the STAT3DAT KO mice? In summary, the present data provide important new insights into how leptin, and other signaling molecules acting through STAT3 in VTA dopamine neurons, can influence physical activity. Endurance training, such as distance running, often induces feelings of well-being and happiness, commonly referred to as ‘‘runner’s high.’’ It will be interesting to determine if reductions in STAT3 signaling in VTA dopamine neurons explains this effect. If so, perhaps inhibitors of STAT3 signaling in VTA will increase willingness to exercise, and increase energy expenditure, in overweight individuals. However, it is not too fanciful to speculate that such inhibitors could boost endurance of distance runners, offering an unfair advance in competitive settings. The findings may also be relevant to anorexia nervosa, a condition associated with low circulating levels of leptin and in which sufferers are often hyperactive and prone to overexercising.
REFERENCES Bates, S.H., Stearns, W.H., Dundon, T.A., Schubert, M., Tso, A.W., Wang, Y., Banks, A.S., Lavery, H.J., Haq, A.K., Maratos-Flier, E., et al. (2003). Nature 421, 856–859. Carr, K.D. (1996). Neurochem. Res. 21, 1455– 1467. Chartoff, E.H., Heusner, C.L., and Palmiter, R.D. (2005). Neuropsychopharmacology 30, 1324– 1333. Fernandes, M.F.A., Matthys, D., Hryhorczuk, C., Sharma, S., Mogra, S., Alquier, T., and Fulton, S. (2015). Cell Metab. 22, this issue, 741–749. Fulton, S., Woodside, B., and Shizgal, P. (2000). Science 287, 125–128. Leinninger, G.M., Jo, Y.H., Leshan, R.L., Louis, G.W., Yang, H., Barrera, J.G., Wilson, H., Opland, D.M., Faouzi, M.A., Gong, Y., et al. (2009). Cell Metab. 10, 89–98. Roberts, M.D., Gilpin, L., Parker, K.E., Childs, T.E., Will, M.J., and Booth, F.W. (2012). Physiol. Behav. 105, 661–668. Tarr, B.A., Kellaway, L.A., St Clair Gibson, A., and Russell, V.A. (2004). Behav. Brain Res. 154, 493–499. Verhagen, L.A., Luijendijk, M.C., and Adan, R.A. (2011). Eur. Neuropsychopharmacol. 21, 274–281.
Beyond Hit-and-Run: Stem Cells Leave a Lasting Memory Kelvin S. Ng,1,2,3 Thomas M. Kuncewicz,1,2,3 and Jeffrey M. Karp1,2,3,* 1Harvard-MIT 2Department
Division of Health Sciences and Technology, Cambridge, MA 02139, USA of Medicine, Division of Biomedical Engineering, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115,
USA 3Harvard Stem Cell Institute, Cambridge, MA 02138, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2015.09.019
While mesenchymal stem cells (MSCs) are rapidly cleared from the body following systemic transplantation, their therapeutic benefits typically persist. In this issue, Liu et al. (2015) reveal that the ability of transplanted MSCs to alleviate osteoporosis in systemic lupus erythematosus is maintained through epigenetic changes conferred by secretory action of the MSCs. The promise of cell therapy in replacing or regenerating damaged tissues and returning tissue to homeostasis has ushered in hundreds of clinical trials including >500 that employ mesenchymal stem cells (MSCs). MSCs differentiate into osteogenic, chondrogenic, and adipo-
genic lineages and are also appreciated for their immunomodulatory properties and ability to evade host immune attack (Ankrum et al., 2014). Despite their immune-evasiveness, transplanted MSCs fail to persist in vivo and are thought to impart therapeutic benefits via a ‘‘hit-
and-run’’ mechanism (von Bahr et al., 2012). Interestingly, these benefits remain detectable long after the transplanted MSCs disappear (Gnecchi et al., 2008; Ranganath et al., 2012; von Bahr et al., 2012). Multiple studies have demonstrated that MSC-conditioned media
Cell Metabolism 22, October 6, 2015 ª2015 Elsevier Inc. 541
Previews Running on Empty: Leptin Signaling in VTA Regulates Reward from Physical Activity Zuxin Chen1 and Paul J. Kenny1,* 1Department of Pharmacology & Systems Therapeutics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2015.09.021
Hunger increases physical activity and stamina to support food-directed foraging behaviors, but underlying mechanisms are unclear. In this issue, Fernandes et al. (2015) show that disruption of leptin-regulated STAT3 signaling in midbrain dopamine neurons increases the rewarding effects of running in mice, which could explain the ‘‘high’’ experienced by endurance runners. It might be expected that hungry animals reduce their energy expenditure to conserve already depleted energy reserves. However, humans and rodents often increase physical activity when hungry. Hunger also increases sensitivity of brain reward systems (Carr, 1996). Conceptually, this increase in reward function serves to enhance the motivational value of physical activity, which in turn facilitates foraging behaviors, and increases pleasure derived from successful foraging, a powerful combination in the context of food seeking. Currently, it is unclear how energy balance is coupled to physical activity. Also unclear is whether the same brain systems regulate the enhanced rewarding value of physical activity and food during hunger states. Circulating leptin levels are usually reduced in hungry animals, which promotes physical activity when food is limited. Infusion of leptin into the ventral tegmental area (VTA), a brain site in which dopamine-containing neurons play a key role in regulating motivated behaviors, suppresses hyperactivity during starvation (Verhagen et al., 2011). This suggests that leptin signaling in the VTA may link energy status to physical activity. In this issue, Fernandes et al. (2015) provide compelling evidence supporting this hypothesis. Leptin acts in neurons primarily through STAT3 (signal transducer and activator of transcription 3) (Bates et al., 2003). To investigate the role for dopamine neurons in regulating the behavioral actions of leptin, Fernandes et al. (2015) conditionally deleted STAT3 in these neurons. This was accomplished by crossing mice
with loxP sites flanking exon 22 of the STAT3 gene with those expressing Cre recombinase under the control of the dopamine transporter gene (DAT), thereby generating STAT3DAT knockout (KO) mice. Although daily food intake, heat dissipation, and respiratory exchange were not impacted, the body weight of STAT3DAT KO mice was significantly lower than control mice. This effect was explained by a dramatic increase in their physical activity. When a running wheel was made available, the KO mice ran almost twice as much as control mice (11 versus 6 km day 1). This increase in physical activity is unlikely to be explained by alterations in anxiety-related behaviors, as KO and control mice demonstrated similar behavior in an elevated-plus maze and open field. Importantly, virus-mediated re-expression of STAT3 selectively in VTA dopamine neurons normalized running behavior in the conditional KO mice, confirming their role in the observed effects. The findings suggest that leptin, acting through STAT3 in VTA dopamine neurons, controls levels of physical activity in mice. Next, the authors investigated the mechanisms by which STAT3 controls running. Using a place conditioning procedure, they found that STAT3DAT KO mice spent far more time than controls exploring an environment in which a running wheel was previously available. This suggests that the rewarding properties of running were greatly potentiated in the KO mice. Interestingly, STAT3DAT KO mice did not demonstrate any evidence for altered sensitivity to rewarding properties of palatable food. Anorectic responses to leptin were also unaltered in the KO mice. This
540 Cell Metabolism 22, October 6, 2015 ª2015 Elsevier Inc.
provides strong evidence that STAT3 signaling in VTA inhibits the rewarding properties of physical activity, but not food, and raises the interesting issue of where in the brain leptin acts to regulate food reward. The lateral hypothalamus (LH) is considered a core component of the brain reward system, and its sensitivity to reward is influenced by hunger in a leptin-dependent manner (Fulton et al., 2000). Moreover, leptin was recently shown to activate STAT3 signaling in a population of inhibitory neurons in LH, which suppressed food intake in mice (Leinninger et al., 2009). Interestingly, these leptinresponsive LH neurons directly innervate VTA dopamine neurons (Leinninger et al., 2009). Hence, leptin likely acts in the VTA and LH to control the rewarding effects of physical activity and food, respectively, with these sites sharing close leptin-regulated functional interactions. Finally, the authors investigated mechanisms by which STAT3 signaling in dopamine neurons controls running. Psychomotor stimulants such as amphetamine and cocaine increase locomotor activity by stimulating dopamine transmission in nucleus accumbens (NAc). Dopamine signaling in NAc is hypothesized to regulate the rewarding properties of wheel running (Roberts et al., 2012). It is therefore surprising that the STAT3DAT KO mice demonstrated a profound deficit in evoked dopamine release into the core of the NAc. The KO mice also demonstrated diminished sensitivity to the locomotor stimulant effects of amphetamine and a dopamine D1 receptor agonist. Considering the well-established role for dopamine in regulating motor behavior, these findings appear
Cell Metabolism
Previews counterintuitive. Nevertheless, they are consistent with recent data showing that running distance is inversely correlated with evoked dopamine release in NAc in rats (Tarr et al., 2004) and that hyperlocomotion can occur independent of dopamine transmission in NAc (Chartoff et al., 2005). How does ablation of STAT3 signaling in VTA dopamine neurons, concomitant with reductions in evoked dopamine release in NAc, precipitate such dramatic increases in the rewarding properties of running? The authors offered a tantalizing piece of preliminary evidence suggesting that the STAT3DAT KO mice have reduced pre-prodynorphin mRNA levels in the VTA. Pre-prodynorphin is produced by the so called ‘‘direct pathway’’ medium spiny neurons in striatum, which provide feedback innervation to the midbrain dopamine system. Moreover, it is known that dynorphin, the mature opioid peptide encoded by this precursor gene, stimulates k opioid receptors (KORs) to inhibit locomotor activity. Perhaps reductions in KOR signaling in the VTA, driven by decreases in dopa-
mine release in NAc, stimulates running behavior in a dopamine-independent manner in the STAT3DAT KO mice? In summary, the present data provide important new insights into how leptin, and other signaling molecules acting through STAT3 in VTA dopamine neurons, can influence physical activity. Endurance training, such as distance running, often induces feelings of well-being and happiness, commonly referred to as ‘‘runner’s high.’’ It will be interesting to determine if reductions in STAT3 signaling in VTA dopamine neurons explains this effect. If so, perhaps inhibitors of STAT3 signaling in VTA will increase willingness to exercise, and increase energy expenditure, in overweight individuals. However, it is not too fanciful to speculate that such inhibitors could boost endurance of distance runners, offering an unfair advance in competitive settings. The findings may also be relevant to anorexia nervosa, a condition associated with low circulating levels of leptin and in which sufferers are often hyperactive and prone to overexercising.
REFERENCES Bates, S.H., Stearns, W.H., Dundon, T.A., Schubert, M., Tso, A.W., Wang, Y., Banks, A.S., Lavery, H.J., Haq, A.K., Maratos-Flier, E., et al. (2003). Nature 421, 856–859. Carr, K.D. (1996). Neurochem. Res. 21, 1455– 1467. Chartoff, E.H., Heusner, C.L., and Palmiter, R.D. (2005). Neuropsychopharmacology 30, 1324– 1333. Fernandes, M.F.A., Matthys, D., Hryhorczuk, C., Sharma, S., Mogra, S., Alquier, T., and Fulton, S. (2015). Cell Metab. 22, this issue, 741–749. Fulton, S., Woodside, B., and Shizgal, P. (2000). Science 287, 125–128. Leinninger, G.M., Jo, Y.H., Leshan, R.L., Louis, G.W., Yang, H., Barrera, J.G., Wilson, H., Opland, D.M., Faouzi, M.A., Gong, Y., et al. (2009). Cell Metab. 10, 89–98. Roberts, M.D., Gilpin, L., Parker, K.E., Childs, T.E., Will, M.J., and Booth, F.W. (2012). Physiol. Behav. 105, 661–668. Tarr, B.A., Kellaway, L.A., St Clair Gibson, A., and Russell, V.A. (2004). Behav. Brain Res. 154, 493–499. Verhagen, L.A., Luijendijk, M.C., and Adan, R.A. (2011). Eur. Neuropsychopharmacol. 21, 274–281.
Beyond Hit-and-Run: Stem Cells Leave a Lasting Memory Kelvin S. Ng,1,2,3 Thomas M. Kuncewicz,1,2,3 and Jeffrey M. Karp1,2,3,* 1Harvard-MIT 2Department
Division of Health Sciences and Technology, Cambridge, MA 02139, USA of Medicine, Division of Biomedical Engineering, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115,
USA 3Harvard Stem Cell Institute, Cambridge, MA 02138, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2015.09.019
While mesenchymal stem cells (MSCs) are rapidly cleared from the body following systemic transplantation, their therapeutic benefits typically persist. In this issue, Liu et al. (2015) reveal that the ability of transplanted MSCs to alleviate osteoporosis in systemic lupus erythematosus is maintained through epigenetic changes conferred by secretory action of the MSCs. The promise of cell therapy in replacing or regenerating damaged tissues and returning tissue to homeostasis has ushered in hundreds of clinical trials including >500 that employ mesenchymal stem cells (MSCs). MSCs differentiate into osteogenic, chondrogenic, and adipo-
genic lineages and are also appreciated for their immunomodulatory properties and ability to evade host immune attack (Ankrum et al., 2014). Despite their immune-evasiveness, transplanted MSCs fail to persist in vivo and are thought to impart therapeutic benefits via a ‘‘hit-
and-run’’ mechanism (von Bahr et al., 2012). Interestingly, these benefits remain detectable long after the transplanted MSCs disappear (Gnecchi et al., 2008; Ranganath et al., 2012; von Bahr et al., 2012). Multiple studies have demonstrated that MSC-conditioned media
Cell Metabolism 22, October 6, 2015 ª2015 Elsevier Inc. 541