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Determining Basal Energy Expenditure and the Capacity of Thermogenic Adipocytes to Expend Energy in Obese Mice
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Metabolic adaptation to calorie restriction.

Carlos Guijas1, J Rafael Montenegro-Burke2, Rigo Cintron-Colon3

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Calorie restriction (CR) lowers body temperature to promote health span. However, warm temperatures (thermoneutrality) block this effect, highlighting temperature-sensitive pathways for CR benefits.

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Area of Science:

  • Metabolic pathways
  • Longevity research
  • Thermoregulation

Background:

  • Calorie restriction (CR) extends lifespan and health span in various species.
  • CR-induced hypothermia is a key mediator of these benefits.
  • Thermoneutral housing conditions (30°C) blunt CR's positive effects by inhibiting hypothermia.

Purpose of the Study:

  • To investigate the global metabolic response to CR under standard (22°C) versus thermoneutral (30°C) housing.
  • To identify metabolites and pathways affected by CR and thermoneutrality.
  • To explore pharmacological targets for mimicking CR's hypothermic effects.

Main Methods:

  • Comparative metabolomics analysis of mice under CR at 22°C vs. 30°C.
  • Cognitive computing for metabolite prioritization.
  • Pharmacological interventions targeting the nitric oxide (NO) and leucine enkephalin pathways.

Main Results:

  • Thermoneutrality reversed a significant portion of CR-induced systemic (39%) and hypothalamic (78%) metabolic changes.
  • CR and thermoneutrality impacted pathways regulating fuel utilization and energy expenditure.
  • The citrulline-NO pathway and leucine enkephalin were identified as key regulators of CR-induced hypothermia.

Conclusions:

  • Ambient temperature significantly modulates the metabolic effects of CR.
  • Metabolic pathways affected by thermoneutrality offer potential targets for mimicking CR's health benefits.
  • Nitric oxide and leucine enkephalin are critical in mediating CR's hypothermic effects.