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Norepinephrine controls both torpor initiation and emergence via distinct mechanisms in the mouse.

Swoap SJ, Weinshenker D - PLoS ONE (2008)

Bottom Line: We previously showed that dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), do not reduce circulating leptin upon fasting nor do they enter torpor.These data indicate that sympathetic activation of white fat and suppression of leptin is required for the onset of torpor in the mouse.Hence, NE signaling via beta(3) adrenergic receptors presumably in brown fat is the first neurotransmitter-receptor system identified that is required for normal recovery from torpor.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Williams College, Williamstown, Massachusetts, United States of America. sswoap@williams.edu

ABSTRACT
Some mammals, including laboratory mice, enter torpor in response to food deprivation, and leptin can attenuate these bouts of torpor. We previously showed that dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), do not reduce circulating leptin upon fasting nor do they enter torpor. To test whether the onset of torpor in mice during a fast requires a NE-mediated reduction in circulating leptin, double mutant mice deficient in both leptin (ob/ob) and DBH (DBL MUT) were generated. Upon fasting, control and ob/ob mice entered torpor as assessed by telemetric core T(b) acquisition. While fasting failed to induce torpor in Dbh -/- mice, leptin deficiency bypassed the requirement for NE, as DBL MUT mice readily entered torpor upon fasting. These data indicate that sympathetic activation of white fat and suppression of leptin is required for the onset of torpor in the mouse. Emergence from torpor was severely retarded in DBL MUT mice, revealing a novel, leptin-independent role for NE in torpor recovery. This phenotype was mimicked by administration of a beta(3) adrenergic receptor antagonist to control mice during a torpor bout. Hence, NE signaling via beta(3) adrenergic receptors presumably in brown fat is the first neurotransmitter-receptor system identified that is required for normal recovery from torpor.

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Leptin deficiency restores torpor in Dbh −/− mice.(A) Typical tracings of core body temperature for a 24 hour fasting period are shown for control, ob/ob, Dbh −/− and DBL MUT mice. Fasting was initiated at the beginning of the 12 hour dark cycle, which started at time 0. Dbh −/− mice clearly do not enter torpor with fasting, whereas the DBL MUT mice enter torpor almost immediately after initiation of the fast. (B) The minimum core body temperature during the 24 hour fast was calculated. An ambient temperature of 21°C during the fast is shown. [F(32,3) = 26.71, P<0.0001]. a : p<0.05 vs. control. c : p<0.05 vs. ob/ob. d: p<0.05 vs. DBL MUT. (C) The maximum rates of temperature decline were calculated for all four genotypes during both the fed period, and during a fast over a sliding 30 minute window using the first derivative of core body temperature curves. [F(32,3) = 29.11, P<0.0001]. b : p<0.05 vs. Dbh −/−. c : p<0.05 vs. ob/ob. d: p<0.05 vs. DBL MUT.
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pone-0004038-g002: Leptin deficiency restores torpor in Dbh −/− mice.(A) Typical tracings of core body temperature for a 24 hour fasting period are shown for control, ob/ob, Dbh −/− and DBL MUT mice. Fasting was initiated at the beginning of the 12 hour dark cycle, which started at time 0. Dbh −/− mice clearly do not enter torpor with fasting, whereas the DBL MUT mice enter torpor almost immediately after initiation of the fast. (B) The minimum core body temperature during the 24 hour fast was calculated. An ambient temperature of 21°C during the fast is shown. [F(32,3) = 26.71, P<0.0001]. a : p<0.05 vs. control. c : p<0.05 vs. ob/ob. d: p<0.05 vs. DBL MUT. (C) The maximum rates of temperature decline were calculated for all four genotypes during both the fed period, and during a fast over a sliding 30 minute window using the first derivative of core body temperature curves. [F(32,3) = 29.11, P<0.0001]. b : p<0.05 vs. Dbh −/−. c : p<0.05 vs. ob/ob. d: p<0.05 vs. DBL MUT.

Mentions: Mice that are deficient in both leptin and DBH are viable following prenatal NE and Epi replacement. These DBL MUT mice are hyperphagic and obese to the same extent as ob/ob mice (Fig. 1). DBL MUT mice are somewhat hypothermic while fed at a Ta of 21°C, with a core Tb ∼1–2°C below that of littermate controls (Table). Mice of all four genotypes (control, Dbh −/−, ob/ob, and DBL MUT) were placed under conditions conducive for torpor (fasted at a Ta of 21°C). Control and ob/ob mice entered torpor bouts as assessed by core Tb measurements (Fig. 2A). As we have shown previously [10], Dbh−/− mice did not enter torpor upon fasting (Fig. 2A). DBL MUT mice, however, experienced a significant bout of hypothermia when fasted that displayed many characteristics of torpor. The depth of hypothermia was similar between control, ob/ob, and the DBL MUT mice, ∼3°C above ambient temperature (Fig. 2B). The rate of entry into torpor was slower for ob/ob mice than control mice (Fig. 2C), likely due to the larger size of the ob/ob mice. The rate of entry into torpor for the DBL MUT was intermediate between the similar-sized ob/ob mouse and the Dbh −/− mouse, which did not enter torpor (Fig. 2C). DBL MUT mice entered torpor almost immediately upon fasting (see Fig. 2A) and reached their maximum rate of Tb decline within 1.8±0.3 hours of fasting, whereas ob/ob and control mice reached their maximum rate of Tb decline after 6.0±0.4 hours and 7.5±0.6 hours from the onset of the fast, respectively.


Norepinephrine controls both torpor initiation and emergence via distinct mechanisms in the mouse.

Swoap SJ, Weinshenker D - PLoS ONE (2008)

Leptin deficiency restores torpor in Dbh −/− mice.(A) Typical tracings of core body temperature for a 24 hour fasting period are shown for control, ob/ob, Dbh −/− and DBL MUT mice. Fasting was initiated at the beginning of the 12 hour dark cycle, which started at time 0. Dbh −/− mice clearly do not enter torpor with fasting, whereas the DBL MUT mice enter torpor almost immediately after initiation of the fast. (B) The minimum core body temperature during the 24 hour fast was calculated. An ambient temperature of 21°C during the fast is shown. [F(32,3) = 26.71, P<0.0001]. a : p<0.05 vs. control. c : p<0.05 vs. ob/ob. d: p<0.05 vs. DBL MUT. (C) The maximum rates of temperature decline were calculated for all four genotypes during both the fed period, and during a fast over a sliding 30 minute window using the first derivative of core body temperature curves. [F(32,3) = 29.11, P<0.0001]. b : p<0.05 vs. Dbh −/−. c : p<0.05 vs. ob/ob. d: p<0.05 vs. DBL MUT.
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pone-0004038-g002: Leptin deficiency restores torpor in Dbh −/− mice.(A) Typical tracings of core body temperature for a 24 hour fasting period are shown for control, ob/ob, Dbh −/− and DBL MUT mice. Fasting was initiated at the beginning of the 12 hour dark cycle, which started at time 0. Dbh −/− mice clearly do not enter torpor with fasting, whereas the DBL MUT mice enter torpor almost immediately after initiation of the fast. (B) The minimum core body temperature during the 24 hour fast was calculated. An ambient temperature of 21°C during the fast is shown. [F(32,3) = 26.71, P<0.0001]. a : p<0.05 vs. control. c : p<0.05 vs. ob/ob. d: p<0.05 vs. DBL MUT. (C) The maximum rates of temperature decline were calculated for all four genotypes during both the fed period, and during a fast over a sliding 30 minute window using the first derivative of core body temperature curves. [F(32,3) = 29.11, P<0.0001]. b : p<0.05 vs. Dbh −/−. c : p<0.05 vs. ob/ob. d: p<0.05 vs. DBL MUT.
Mentions: Mice that are deficient in both leptin and DBH are viable following prenatal NE and Epi replacement. These DBL MUT mice are hyperphagic and obese to the same extent as ob/ob mice (Fig. 1). DBL MUT mice are somewhat hypothermic while fed at a Ta of 21°C, with a core Tb ∼1–2°C below that of littermate controls (Table). Mice of all four genotypes (control, Dbh −/−, ob/ob, and DBL MUT) were placed under conditions conducive for torpor (fasted at a Ta of 21°C). Control and ob/ob mice entered torpor bouts as assessed by core Tb measurements (Fig. 2A). As we have shown previously [10], Dbh−/− mice did not enter torpor upon fasting (Fig. 2A). DBL MUT mice, however, experienced a significant bout of hypothermia when fasted that displayed many characteristics of torpor. The depth of hypothermia was similar between control, ob/ob, and the DBL MUT mice, ∼3°C above ambient temperature (Fig. 2B). The rate of entry into torpor was slower for ob/ob mice than control mice (Fig. 2C), likely due to the larger size of the ob/ob mice. The rate of entry into torpor for the DBL MUT was intermediate between the similar-sized ob/ob mouse and the Dbh −/− mouse, which did not enter torpor (Fig. 2C). DBL MUT mice entered torpor almost immediately upon fasting (see Fig. 2A) and reached their maximum rate of Tb decline within 1.8±0.3 hours of fasting, whereas ob/ob and control mice reached their maximum rate of Tb decline after 6.0±0.4 hours and 7.5±0.6 hours from the onset of the fast, respectively.

Bottom Line: We previously showed that dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), do not reduce circulating leptin upon fasting nor do they enter torpor.These data indicate that sympathetic activation of white fat and suppression of leptin is required for the onset of torpor in the mouse.Hence, NE signaling via beta(3) adrenergic receptors presumably in brown fat is the first neurotransmitter-receptor system identified that is required for normal recovery from torpor.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Williams College, Williamstown, Massachusetts, United States of America. sswoap@williams.edu

ABSTRACT
Some mammals, including laboratory mice, enter torpor in response to food deprivation, and leptin can attenuate these bouts of torpor. We previously showed that dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), do not reduce circulating leptin upon fasting nor do they enter torpor. To test whether the onset of torpor in mice during a fast requires a NE-mediated reduction in circulating leptin, double mutant mice deficient in both leptin (ob/ob) and DBH (DBL MUT) were generated. Upon fasting, control and ob/ob mice entered torpor as assessed by telemetric core T(b) acquisition. While fasting failed to induce torpor in Dbh -/- mice, leptin deficiency bypassed the requirement for NE, as DBL MUT mice readily entered torpor upon fasting. These data indicate that sympathetic activation of white fat and suppression of leptin is required for the onset of torpor in the mouse. Emergence from torpor was severely retarded in DBL MUT mice, revealing a novel, leptin-independent role for NE in torpor recovery. This phenotype was mimicked by administration of a beta(3) adrenergic receptor antagonist to control mice during a torpor bout. Hence, NE signaling via beta(3) adrenergic receptors presumably in brown fat is the first neurotransmitter-receptor system identified that is required for normal recovery from torpor.

Show MeSH
Related in: MedlinePlus