Review Article | Published:

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

Abstract

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

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Ogden CL et al. (2002) Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 288: 1728–1732

  2. 2

    Hill JO et al. (2003) Obesity and the environment: where do we go from here? Science 299: 853–855

  3. 3

    Ebbeling CB et al. (2002) Childhood obesity: public-health crisis, common sense cure. Lancet 360: 473–482

  4. 4

    Troiano RP et al. (2000) Energy and fat intakes of children and adolescents in the United States: data from the National Health and Nutrition Examination Surveys. Am J Clin Nutr 72 (Suppl): 1343S–1353S

  5. 5

    Kimm SYS et al. (2002) Decline in physical activity in black girls and white girls in adolescence. N Engl J Med 347: 709–715

  6. 6

    Schwimmer JB et al. (2003) Health-related quality of life of severely obese children and adolescents. JAMA 289: 1813–1819

  7. 7

    Epstein LH et al. (2001) Behavioral therapy in the treatment of pediatric obesity. Pediatr Clin North Am 48: 981–993

  8. 8

    Ritchie L et al. (2001) Pediatric overweight: a review of the literature [http://www.cnr.berkeley.edu/cwh/PDFs/Full_COPI_secure.pdf] (accessed 17 May 2006)

  9. 9

    Lustig RH (2001) The neuroendocrinology of childhood obesity. Pediatr Clin North Am 48: 909–930

  10. 10

    Balthasar N et al. (2005) Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123: 493–505

  11. 11

    Lustig RH The efferent arm of the energy balance regulatory pathway: neuroendocrinology and pathology. In Obesity and Energy Metabolism: Research and Clinical Applications (Ed Donahoue PA) New Jersey: Humana, in press

  12. 12

    Porte D et al. (2005) Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes 54: 1264–1276

  13. 13

    Flier JS (1998) What's in a name? In search of leptin's physiologic role. J Clin Endocrinol Metab 83: 1407–1413

  14. 14

    Mark AL et al. (2003) A leptin-sympathetic-leptin feedback loop: potential implications for regulation of arterial pressure and body fat. Acta Physiol Scand 177: 345–349

  15. 15

    Baskin DG et al. (1988) Insulin and insulin-like growth factors in the CNS. Trends Neurosci 11: 107–111

  16. 16

    Schwartz MW et al. (1990) Insulin binding to brain capillaries is reduced in genetically obese, hyperinsulinemic Zucker rats. Peptides 11: 467–472

  17. 17

    Muntzel MS et al. (1994) Intracerebroventricular insulin produces nonuniform regional increases in sympathetic nerve activity. Am J Physiol 267 (Pt 2): R1350–R1355

  18. 18

    Niswender KD et al. (2001) Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 413: 794–795

  19. 19

    Brüning JC et al. (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289: 2122–2125

  20. 20

    Kubota N et al. (2004) Insulin receptor substrate 2 plays a crucial role in β cells and the hypothalamus. J Clin Invest 114: 917–927

  21. 21

    Choudhury AI et al. (2005) The role of insulin receptor substrate 2 in hypothalamic and beta cell function. J Clin Invest 115: 940–950

  22. 22

    Niswender KD and Schwartz MW (2003) Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Front Neuroendocrinol 24: 1–10

  23. 23

    Lowell BB and Spiegelman BM (2000) Towards a molecular understanding of adaptive thermogenesis. Nature 404: 652–660

  24. 24

    Collins S et al. (1996) Role of leptin in fat regulation [letter]. Nature 380: 677

  25. 25

    Haynes WG et al. (1997) Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 100: 270–278

  26. 26

    Blaak EE et al. (1993) Adrenoceptor subtypes mediating catecholamine-induced thermogenesis in man. Int J Obes Relat Metab Disord 17 (Suppl 3): S78–S81

  27. 27

    Kreier F et al. (2002) Selective parasympathetic innervation of subcutaneous and intra-abdominal fat-functional implications. J Clin Invest 110: 1243–1250

  28. 28

    Lustig RH (2003) Autonomic dysfunction of the β-cell and the pathogenesis of obesity. Rev Endocr Metab Disord 4: 23–32

  29. 29

    Yamada M et al. (2001) Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature 410: 207–212

  30. 30

    Bray GA and Greenway FL (1999) Current and potential drugs for treatment of obesity. Endocr Rev 20: 805–875

  31. 31

    Leibel RL et al. (1995) Changes in energy expenditure resulting from altered body weight. N Engl J Med 332: 621–628

  32. 32

    Rosenbaum M et al. (1997) Effects of weight change on plasma leptin concentrations and energy expenditure. J Clin Endocrinol Metab 82: 3647–3654

  33. 33

    Rosenbaum M et al. (2003) Effects of experimental weight perturbation on skeletal muscle work efficiency in human subjects. Am J Physiol Regul Integr Comp Physiol 285: R183–R192

  34. 34

    Smit HJ et al. (2004) Mood and cognitive performance effects of “energy” drink constituents: caffeine, glucose, and carbonation. Nutr Neurosci 7: 127–139

  35. 35

    Belza A and Jessen AB (2005) Bioactive food stimulants of sympathetic activity: effect on 24-h energy expenditure and fat oxidation. Eur J Clin Nutr 59: 733–741

  36. 36

    Boden G et al. (1996) Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab 81: 454–458

  37. 37

    Aronne LJ et al. (1995) Autonomic nervous system activity in weight gain and weight loss. Am J Physiol 269: R222–R225

  38. 38

    Farooqi IS et al. (2002) Beneficial effects of leptin on obesity, T-cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110: 1093–1103

  39. 39

    Lee HC et al. (1989) Direct effect of CNS on insulin hypersecretion in obese Zucker rats: involvement of vagus nerve. Am J Physiol 256: E439–E444

  40. 40

    van Dijk G et al. (2005) Reduced anorexigenic efficacy of leptin, but not of the melanocortin receptor agonist melanotan-II, predicts diet-induced obesity in rats. Endocrinology 146: 5247–5256

  41. 41

    Heymsfield SB et al. (1999) Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282: 1568–1575

  42. 42

    Poretti A et al. (2004) Outcome of craniopharyngioma in children: long-term complications and quality of life. Dev Med Child Neurol 46: 220–229

  43. 43

    Lustig RH et al. (2003) Risk factors for the development of obesity in children surviving brain tumors. J Clin Endocrinol Metab 88: 611–616

  44. 44

    Schofl C et al. (2002) Sympathoadrenal counterregulation in patients with hypothalamic craniopharyngioma. J Clin Endocrinol Metab 87: 624–629

  45. 45

    Harz KJ et al. (2003) Obesity in patients with craniopharyngioma: assessment of food intake and movement counts indicating physical activity. J Clin Endocrinol Metab 88: 5227–5231

  46. 46

    Rosenbaum M et al. (2002) Low dose leptin administration reverses effects of sustained weight reduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab 87: 2391–2394

  47. 47

    Bray GA and Gallagher TF (1975) Manifestations of hypothalamic obesity in man: a comprehensive investigation of eight patients and a review of the literature. Medicine (Baltimore) 54: 301–333

  48. 48

    Lustig RH et al. (1999) Hypothalamic obesity in children caused by cranial insult: altered glucose and insulin dynamics, and reversal by a somatostatin agonist. J Pediatr 135: 162–168

  49. 49

    Lustig RH et al. (2003) Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial. J Clin Endocrinol Metab 88: 2586–2592

  50. 50

    Velasquez-Mieyer PA et al. (2003) Suppression of insulin secretion promotes weight loss and alters macronutrient preference in a subset of obese adults. Int J Obesity 27: 219–226

  51. 51

    Lustig RH et al. (2004) Obesity, leptin resistance, and the effects of insulin suppression. Int J Obesity 28: 1344–1348

  52. 52

    Lustig RH et al. (2006) A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion. Int J Obes 30: 331–341

  53. 53

    El-Haschimi K et al. (2000) Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 105: 1827–1832

  54. 54

    Clegg DJ et al. (2005) Reduced anorexic effects of insulin in obesity-prone rats fed a moderate fat diet. Am J Physiol Regul Integr Comp Physiol 288: R981–R986

  55. 55

    Mori H et al. (2004) Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 10: 739–743

  56. 56

    Munzberg H and Myers MG (2005) Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 8: 566–570

  57. 57

    Emanuelli B et al. (2000) SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem 275: 15985–15991

  58. 58

    Banks W et al. (1999) Impaired transport of leptin across the blood-brain barrier in obesity. Peptides 20: 1341–1345

  59. 59

    Ishihara Y et al. (2004) Effects of diet and time of the day on serum and CSF leptin levels in Osborne-Mendel and S5B/Pl rats. Obes Res 12: 1067–1076

  60. 60

    Nam SY et al. (2001) Cerebrospinal fluid and plasma concentrations of leptin, NPY, and α-MSH in obese women and their relationship to negative energy balance. J Clin Endocrinol Metab 86: 4849–4853

  61. 61

    Figlewicz DP et al. (1996) Review article: endocrine regulation of food intake and body weight. J Lab Clin Med 127: 328–332

  62. 62

    Zabolotny JM et al. (2002) PTP1B regulates leptin signal transduction in vivo. Dev Cell 2: 489–495

  63. 63

    Flier JS (2004) Obesity wars: molecular progress confronts an expanding epidemic. Cell 116: 337–350

  64. 64

    Li HJ et al. (2005) A twin study for serum leptin, soluble leptin receptor, and free insulin-like growth factor-1 in pubertal females. J Clin Endocrinol Metab 90: 3659–3664

  65. 65

    McLachlan KA et al. (2006) Do adiponectin, TNFα, leptin, and CRP relate to insulin resistance in pregnancy? Studies in women with and without gestational diabetes, during and after pregnancy. Diab Metab Res Rev 22: 131–138

  66. 66

    Castracane VD et al. (2005) Serum leptin in nonpregnant and pregnant women and in old and new world nonhuman primates. Exp Biol Med 230: 251–254

  67. 67

    Kelley AE et al. (2002) Opioid modulation of taste hedonics within the ventral striatum. Physiol Behav 76: 365–377

  68. 68

    Shalev U et al. (2001) Leptin attenuates food deprivation-induced relapse to heroin seeking. J Neurosci 21: RC129

  69. 69

    Carr KD et al. (2003) Evidence of increased dopamine receptor signaling in food-restricted rats. Neuroscience 119: 1157–1167

  70. 70

    Wang GJ et al. (2001) Brain dopamine and obesity. Lancet 357: 354–357

  71. 71

    Figlewicz DP et al. (1994) Intraventricular insulin increases dopaminergic transporter mRNA in rat VTA/substantia nigra. Brain Res 644: 331–334

  72. 72

    Sipols AJ et al. (2002) Intraventricular insulin decreases kappa opioid-mediated sucrose intake in rats. Peptides 23: 2181–2187

  73. 73

    Figlewicz DP (2003) Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am J Phyisol Regul Integ Comp Physiol 284: R882–R892

  74. 74

    Arslanian SA et al. (2002) Hyperinsulinemia in African-American children. Decreased insulin clearance and increased insulin secretion and its relationship to insulin sensitivity. Diabetes 51: 3014–3019

  75. 75

    Preeyasombat C et al. (2005) Racial and etiopathologic dichotomies in insulin secretion and resistance in obese children. J Pediatr 146: 474–481

  76. 76

    Stocker CJ et al. (2005) Fetal origins of insulin resistance and obesity. Proc Nutr Soc 64: 143–151

  77. 77

    Yajnik CS et al. (2002) Adiposity and hyperinsulinemia in Indians are present at birth. J Clin Endocrinol Metab 87: 5575–5580

  78. 78

    Hofman PL et al. (2004) Premature birth and later insulin resistance. N Engl J Med 351: 2179–2186

  79. 79

    Cettour-Rose P et al. (2005) Redistribution of glucose from skeletal muscle to adipose tissue during catch-up fat: a link between catch-up growth and later metabolic syndrome. Diabetes 54: 751–756

  80. 80

    Isganaitis E and Lustig RH (2005) Fast food, central nervous system insulin resistance, and obesity. Arterioscler Thromb Vasc Biol 25: 2451–2462

Download references

Acknowledgements

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.

Author information

Competing interests

The author declares no competing financial interests.

Correspondence to Robert H Lustig.

Rights and permissions

Reprints and Permissions

About this article

Further reading

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