Leptin replacement improves cognitive development

Gilberto J Paz-Filho, Talin Babikian, Robert Asarnow, Tuncay Delibasi, Karin Esposito, Halil K Erol, Ma-Li Wong, Julio Licinio, Gilberto J Paz-Filho, Talin Babikian, Robert Asarnow, Tuncay Delibasi, Karin Esposito, Halil K Erol, Ma-Li Wong, Julio Licinio

Abstract

Background: Leptin changes brain structure, neuron excitability and synaptic plasticity. It also regulates the development and function of feeding circuits. However, the effects of leptin on neurocognitive development are unknown.

Objective: To evaluate the effect of leptin on neurocognitive development.

Methodology: A 5-year-old boy with a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) was treated with recombinant methionyl human leptin (r-metHuLeptin) at physiologic replacement doses of 0.03 mg/kg/day. Cognitive development was assessed using the Differential Ability Scales (DAS), a measure of general verbal and nonverbal functioning; and selected subtests from the NEPSY, a measure of neuropsychological functioning in children.

Principal findings: Prior to treatment, the patient was morbidly obese, hypertensive, dyslipidemic, and hyperinsulinemic. Baseline neurocognitive tests revealed slower than expected rates of development (developmental age lower than chronological age) in a majority of the areas assessed. After two years, substantial increases in the rates of development in most neurocognitive domains were apparent, with some skills at or exceeding expectations based on chronological age. We also observed marked weight loss and resolution of hypertension, dyslipidemia and hyperinsulinemia.

Conclusions: We concluded that replacement with r-metHuLeptin is associated with weight loss and changes in rates of development in many neurocognitive domains, which lends support to the hypothesis that, in addition to its role in metabolism, leptin may have a cognitive enhancing role in the developing central nervous system.

Trial registration: ClinicalTrials.gov NCT00659828.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Rates of development for DAS…
Figure 1. Rates of development for DAS subtests.
A rate of “1” (vertical axis) indicates typical development (i.e., developmental age equals chronological age). For example, at age 4, performance at the level of a 4 year old would yield a rate of development of 1 (4/4). In contrast, at age 4, a performance at the level of a 3 year old would yield a developmental rate of 0.75 (3/4). Subsequently, a score of

Figure 2. Rates of development for NEPSY…

Figure 2. Rates of development for NEPSY subtests.

A rate of “1” (vertical axis) indicates…

Figure 2. Rates of development for NEPSY subtests.
A rate of “1” (vertical axis) indicates typical development (i.e., developmental age matches chronological age). A score of

Figure 3. Patient before replacement with r-metHuLeptin…

Figure 3. Patient before replacement with r-metHuLeptin at age 5y1m and during treatment at age…

Figure 3. Patient before replacement with r-metHuLeptin at age 5y1m and during treatment at age 7y2m.
Similar articles
Cited by
References
    1. Bluher S, Mantzoros CS. Leptin in reproduction. Curr Opin Endocrinol Diabetes Obes. 2007;14:458–464. - PubMed
    1. Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet. 2005;366:74–85. - PubMed
    1. Ceddia RB. Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis. Int J Obes (Lond) 2005;29:1175–1183. - PubMed
    1. Brennan AM, Mantzoros CS. Leptin and adiponectin: their role in diabetes. Curr Diab Rep. 2007;7:1–2. - PubMed
    1. Karsenty G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab. 2006;4:341–348. - PubMed
Show all 59 references
Publication types
MeSH terms
Associated data
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 2. Rates of development for NEPSY…
Figure 2. Rates of development for NEPSY subtests.
A rate of “1” (vertical axis) indicates typical development (i.e., developmental age matches chronological age). A score of

Figure 3. Patient before replacement with r-metHuLeptin…

Figure 3. Patient before replacement with r-metHuLeptin at age 5y1m and during treatment at age…

Figure 3. Patient before replacement with r-metHuLeptin at age 5y1m and during treatment at age 7y2m.
Figure 3. Patient before replacement with r-metHuLeptin…
Figure 3. Patient before replacement with r-metHuLeptin at age 5y1m and during treatment at age 7y2m.

References

    1. Bluher S, Mantzoros CS. Leptin in reproduction. Curr Opin Endocrinol Diabetes Obes. 2007;14:458–464.
    1. Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet. 2005;366:74–85.
    1. Ceddia RB. Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis. Int J Obes (Lond) 2005;29:1175–1183.
    1. Brennan AM, Mantzoros CS. Leptin and adiponectin: their role in diabetes. Curr Diab Rep. 2007;7:1–2.
    1. Karsenty G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab. 2006;4:341–348.
    1. Cock TA, Auwerx J. Leptin: cutting the fat off the bone. Lancet. 2003;362:1572–1574.
    1. Barouch LA, Berkowitz DE, Harrison RW, O'Donnell CP, Hare JM. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation. 2003;108:754–759.
    1. Otero M, Lago R, Lago F, Casanueva FF, Dieguez C, et al. Leptin, from fat to inflammation: old questions and new insights. FEBS Lett. 2005;579:295–301.
    1. Ahima RS. Adipose tissue as an endocrine organ. Obesity (Silver Spring) 2006;14(Suppl 5):242S–249S.
    1. Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest. 2003;111:1409–1421.
    1. Lago F, Dieguez C, Gomez-Reino J, Gualillo O. Adipokines as emerging mediators of immune response and inflammation. Nat Clin Pract Rheumatol. 2007;3:716–724.
    1. La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol. 2004;4:371–379.
    1. Matochik JA, London ED, Yildiz BO, Ozata M, Caglayan S, et al. Effect of leptin replacement on brain structure in genetically leptin-deficient adults. J Clin Endocrinol Metab. 2005;90:2851–2854.
    1. Baicy K, London ED, Monterosso J, Wong ML, Delibasi T, et al. Leptin replacement alters brain response to food cues in genetically leptin-deficient adults. Proc Natl Acad Sci U S A. 2007;104:18276–18279.
    1. Farooqi IS, Bullmore E, Keogh J, Gillard J, O'Rahilly S, et al. Leptin regulates striatal regions and human eating behavior. Science. 2007;317:1355.
    1. Harvey J. Leptin regulation of neuronal excitability and cognitive function. Curr Opin Pharmacol. 2007;7:643–647.
    1. Harvey J, Shanley LJ, O'Malley D, Irving AJ. Leptin: a potential cognitive enhancer? Biochem Soc Trans. 2005;33:1029–1032.
    1. Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science. 2004;304:110–115.
    1. Bouret SG, Simerly RB. Minireview: Leptin and development of hypothalamic feeding circuits. Endocrinology. 2004;145:2621–2626.
    1. Udagawa J, Hashimoto R, Hioki K, Otani H. The role of leptin in the development of the cortical neuron in mouse embryos. Brain Res. 2006;1120:74–82.
    1. Udagawa J, Nimura M, Otani H. Leptin affects oligodendroglial development in the mouse embryonic cerebral cortex. Neuro Endocrinol Lett. 2006;27:177–182.
    1. Licinio J, Milane M, Thakur S, Whelan F, Yildiz BO, et al. Effects of leptin on intake of specific micro- and macronutrients in a woman with leptin gene deficiency studied off and on leptin at stable body weight. Appetite. 2007;49:594–599.
    1. Licinio J, Ribeiro L, Busnello JV, Delibasi T, Thakur S, et al. Effects of leptin replacement on macro- and micronutrient preferences. Int J Obes (Lond) 2007;31:1859–1863.
    1. Williamson DA, Ravussin E, Wong ML, Wagner A, Dipaoli A, et al. Microanalysis of eating behavior of three leptin deficient adults treated with leptin therapy. Appetite. 2005;45:75–80.
    1. Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci U S A. 2004;101:4531–4536.
    1. O'Rahilly S. Human obesity and insulin resistance: lessons from experiments of nature. Biochem Soc Trans. 2007;35:33–36.
    1. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387:903–908.
    1. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998;18:213–215.
    1. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002;110:1093–1103.
    1. Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, et al. Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab. 2004;89:4821–4826.
    1. Butler MG, Moore J, Morawiecki A, Nicolson M. Comparison of leptin protein levels in Prader-Willi syndrome and control individuals. Am J Med Genet. 1998;75:7–12.
    1. Ellis KJ, Nicolson M. Leptin levels and body fatness in children: effects of gender, ethnicity, and sexual development. Pediatr Res. 1997;42:484–488.
    1. Mantzoros CS, Ozata M, Negrao AB, Suchard MA, Ziotopoulou M, et al. Synchronicity of frequently sampled thyrotropin (TSH) and leptin concentrations in healthy adults and leptin-deficient subjects: evidence for possible partial TSH regulation by leptin in humans. J Clin Endocrinol Metab. 2001;86:3284–3291.
    1. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114:555–576.
    1. Harvey J, Ashford ML. Leptin in the CNS: much more than a satiety signal. Neuropharmacology. 2003;44:845–854.
    1. Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, et al. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience. 2002;113:607–615.
    1. Harvey J. Novel actions of leptin in the hippocampus. Ann Med. 2003;35:197–206.
    1. Garza JC, Guo M, Zhang W, Lu XY. Leptin increases adult hippocampal neurogenesis in vivo and in vitro. J Biol Chem. 2008;283:18238–18247.
    1. Winocur G, Greenwood CE, Piroli GG, Grillo CA, Reznikov LR, et al. Memory impairment in obese Zucker rats: an investigation of cognitive function in an animal model of insulin resistance and obesity. Behav Neurosci. 2005;119:1389–1395.
    1. Ahima RS, Bjorbaek C, Osei S, Flier JS. Regulation of neuronal and glial proteins by leptin: implications for brain development. Endocrinology. 1999;140:2755–2762.
    1. Steppan CM, Swick AG. A role for leptin in brain development. Biochem Biophys Res Commun. 1999;256:600–602.
    1. Sena A, Sarlieve LL, Rebel G. Brain myelin of genetically obese mice. J Neurol Sci. 1985;68:233–243.
    1. Bereiter DA, Jeanrenaud B. Altered neuroanatomical organization in the central nervous system of the genetically obese (ob/ob) mouse. Brain Res. 1979;165:249–260.
    1. Bereiter DA, Jeanrenaud B. Altered dendritic orientation of hypothalamic neurons from genetically obese (ob/ob) mice. Brain Res. 1980;202:201–206.
    1. Petridou E, Mantzoros CS, Belechri M, Skalkidou A, Dessypris N, et al. Neonatal leptin levels are strongly associated with female gender, birth length, IGF-I levels and formula feeding. Clin Endocrinol (Oxf) 2005;62:366–371.
    1. Kratzsch J, Schubring C, Stitzel B, Bottner A, Berthold A, et al. Inverse changes in the serum levels of the soluble leptin receptor and leptin in neonates: relations to anthropometric data. J Clin Endocrinol Metab. 2005;90:2212–2217.
    1. Alexe DM, Syridou G, Petridou ET. Determinants of early life leptin levels and later life degenerative outcomes. Clin Med Res. 2006;4:326–335.
    1. Proulx K, Richard D, Walker CD. Leptin regulates appetite-related neuropeptides in the hypothalamus of developing rats without affecting food intake. Endocrinology. 2002;143:4683–4692.
    1. Ahima RS, Prabakaran D, Flier JS. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest. 1998;101:1020–1027.
    1. Bouret SG, Draper SJ, Simerly RB. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci. 2004;24:2797–2805.
    1. Bouret SG, Simerly RB. Development of leptin-sensitive circuits. J Neuroendocrinol. 2007;19:575–582.
    1. Ben X, Qin Y, Wu S, Zhang W, Cai W. Placental leptin correlates with intrauterine fetal growth and development. Chin Med J (Engl) 2001;114:636–639.
    1. Udagawa J, Hashimoto R, Suzuki H, Hatta T, Sotomaru Y, et al. The role of leptin in the development of the cerebral cortex in mouse embryos. Endocrinology. 2006;147:647–658.
    1. Walker CD, Long H, Williams S, Richard D. Long-lasting effects of elevated neonatal leptin on rat hippocampal function, synaptic proteins and NMDA receptor subunits. J Neurosci Res. 2007;85:816–828.
    1. Shanley LJ, Irving AJ, Harvey J. Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. J Neurosci. 2001;21:RC186.
    1. Durakoglugil M, Irving AJ, Harvey J. Leptin induces a novel form of NMDA receptor-dependent long-term depression. J Neurochem. 2005;95:396–405.
    1. Harvey J, Solovyova N, Irving A. Leptin and its role in hippocampal synaptic plasticity. Prog Lipid Res. 2006;45:369–378.
    1. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269:540–543.
    1. Seufert J. Leptin effects on pancreatic beta-cell gene expression and function. Diabetes. 2004;53(Suppl 1):S152–158.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner