Childhood obesity: behavioral aberration or biochemical drive? Reinterpreting the First Law of Thermodynamics


Childhood obesity has become epidemic over the past 30 years. The First Law of Thermodynamics is routinely interpreted to imply that weight gain is secondary to increased caloric intake and/or decreased energy expenditure, two behaviors that have been documented during this interval; nonetheless, lifestyle interventions are notoriously ineffective at promoting weight loss. Obesity is characterized by hyperinsulinemia. Although hyperinsulinemia is usually thought to be secondary to obesity, it can instead be primary, due to autonomic dysfunction. Obesity is also a state of leptin resistance, in which defective leptin signal transduction promotes excess energy intake, to maintain normal energy expenditure. Insulin and leptin share a common central signaling pathway, and it seems that insulin functions as an endogenous leptin antagonist. Suppressing insulin ameliorates leptin resistance, with ensuing reduction of caloric intake, increased spontaneous activity, and improved quality of life. Hyperinsulinemia also interferes with dopamine clearance in the ventral tegmental area and nucleus accumbens, promoting increased food reward. Accordingly, the First Law of Thermodynamics can be reinterpreted, such that the behaviors of increased caloric intake and decreased energy expenditure are secondary to obligate weight gain. This weight gain is driven by the hyperinsulinemic state, through three mechanisms: energy partitioning into adipose tissue; interference with leptin signal transduction; and interference with extinction of the hedonic response to food.

Key Points

  • Behavior has biochemical underpinnings, particularly the pathologic behaviors in disease states

  • Obesity is characterized by hyperinsulinemia and leptin resistance

  • In the long term, insulin functions as an endogenous leptin antagonist; it interferes with leptin signal transduction resulting in increased food intake and decreased physical activity

  • Chronic hyperinsulinemia interferes with satiety by preventing extinction of the hedonic response to food

  • Hyperinsulinemia has genetic, epigenetic, and environmental inputs

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Figure 1: The homeostatic pathway of energy balance
Figure 2: Central regulation of leptin signaling, autonomic innervation of adipocytes and β-cells, and the starvation response
Figure 3: Overlap (depicted in black) between insulin and leptin signaling pathways in the ventromedial hypothalamic neuron
Figure 4: Insulin, leptin, reward and obesity


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The author would like to thank Drs WL Miller, MM Grumbach, SH Mellon, MF Dallman, ES Epel, AK Garber, JA Yanovski, and JG Kral for their input to and critique of this work.

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Correspondence to Robert H Lustig.

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Lustig, R. Childhood obesity: behavioral aberration or biochemical drive? Reinterpreting the First Law of Thermodynamics. Nat Rev Endocrinol 2, 447–458 (2006).

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