Printed in U.S.A. Copyright © 1999 by The Endocrine Society Regulation of Neuronal and Glial Proteins by Leptin: Implications for Brain Development*

The complete absence of leptin causes severe obesity in mice and humans, but its physiological roles are incompletely defined. Earlier studies reported decreased brain weight and impaired myelination in ob/ob and db/db mice. Here we have examined the effects of leptin deficiency and postnatal leptin treatment on brain weight, the expression of a broad array of neuronal and glial markers, and locomotor activity. ob/ob and db/db mice have reduced brain weight and an immature pattern of expression of synaptic and glial proteins, with growth-associated protein being elevated in the neocortex and hippocampus, and syntaxin-1, synaptosomal-associated protein-25, and synaptobrevin being decreased. The expression of myelin basic protein, proteolipid protein, and glial fibrillary acidic protein was also decreased in the neocortex, hippocampus, and striatum of ob/ob and db/db mice. Six weeks of leptin treatment initiated at week 4 increased brain weight and protein content, increased locomotor activity, and normalized levels of growth-associated protein, syntaxin-1, and synaptosomal-associated protein-25 in ob/ob mice without affecting synaptobrevin and glial proteins. In contrast with ob/ob and db/db mice, obese agouti (AY/a) mice had normal brain weight and expression of synaptic and glial proteins. These findings suggest that leptin, a peripheral signal of energy stores in adult animals, is required for normal neuronal and glial maturation in the mouse nervous system.

[1]  J. Mayer.  Decreased activity and energy balance in the hereditary obesity-diabetes syndrome of mice. , 1953, Science.

[2]  C. Saper,et al.  Distributions of leptin receptor mRNA isoforms in the rat brain , 1998, The Journal of comparative neurology.

[3]  J. de Vellis,et al.  Differential regulation of oligodendrocyte markers by glucocorticoids: post-transcriptional regulation of both proteolipid protein and myelin basic protein and transcriptional regulation of glycerol phosphate dehydrogenase. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[4]  E. Chapman,et al.  Differential Distribution of Syntaxin Isoforms 1A and 1B in the Rat Central Nervous System , 1996, The European journal of neuroscience.

[5]  N. Hoggard,et al.  Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  H. Joosten,et al.  Growth pattern and behavioral traits associated with the development of the obese-hyperglycemic syndrome in mice (ob-ob). , 1974, Metabolism: clinical and experimental.

[7]  B. Jeanrenaud,et al.  Altered dendritic orientation of hypothalamic neurons from genetically obese (ob/ob) mice , 1980, Brain Research.

[8]  G. Butler-Browne,et al.  Influence of the dwarf mouse mutation on skeletal and cardiac myosin isoforms. Effect of one injection of thyroxine on skeletal and cardiac muscle phenotype. , 1987, The Journal of biological chemistry.

[9]  S. O’Rahilly,et al.  Congenital leptin deficiency is associated with severe early-onset obesity in humans , 1997, Nature.

[10]  G. Speijers,et al.  Brain deviations in adult obese-hyperglycemic mice (ob/ob). , 1979, Metabolism: clinical and experimental.

[11]  K. Mounzih,et al.  Early Onset of Reproductive Function in Normal Female Mice Treated with Leptin , 1997, Science.

[12]  M. Pelleymounter,et al.  Effects of the obese gene product on body weight regulation in ob/ob mice. , 1995, Science.

[13]  J. Flier,et al.  Leptin accelerates the onset of puberty in normal female mice. , 1997, The Journal of clinical investigation.

[14]  J. Flier,et al.  Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. , 1998, The Journal of clinical investigation.

[15]  F. Casanueva,et al.  Regulation of in vivo growth hormone secretion by leptin. , 1997, Endocrinology.

[16]  J. Bernal,et al.  Neonatal hypothyroidism affects the timely expression of myelin-associated glycoprotein in the rat brain. , 1993, The Journal of clinical investigation.

[17]  S. Vannucci,et al.  Glucose utilization and glucose transporter proteins GLUT-1 and GLUT-3 in brains of diabetic (db/db) mice. , 1997, The American journal of physiology.

[18]  H. Snodgrass,et al.  Leptin stimulates fetal and adult erythroid and myeloid development. , 1997, Blood.

[19]  R. Schwarcz,et al.  Neuronal damage after the injection of amino-oxyacetic acid into the rat entorhinal cortex: a silver impregnation study , 1997, Neuroscience.

[20]  K. Polonsky,et al.  Leptin, the obese gene product, rapidly modulates synaptic transmission in the hypothalamus. , 1996, Molecular pharmacology.

[21]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[22]  G. Chaouat,et al.  A progesterone-induced blocking factor corrects high resorption rates in mice treated with antiprogesterone. , 1990, American journal of obstetrics and gynecology.

[23]  J. Halaas,et al.  Leptin and the regulation of body weight in mammals , 1998, Nature.

[24]  R. Skoda,et al.  Leptin Receptor Immunoreactivity in Chemically Defined Target Neurons of the Hypothalamus , 1998, The Journal of Neuroscience.

[25]  R. Scheller,et al.  n-Sec1: a neural-specific syntaxin-binding protein. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[26]  G. Bray,et al.  Adrenalectomy and food restriction in the genetically obese (ob/ob) mouse. , 1984, The American journal of physiology.

[27]  J. Flier,et al.  Clinical review 94: What's in a name? In search of leptin's physiologic role. , 1998, The Journal of clinical endocrinology and metabolism.

[28]  B. McEwen,et al.  Steroid hormones: effect on brain development and function. , 1992, Hormone research.

[29]  K. Clément,et al.  A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction , 1998, Nature.

[30]  G. Rebel,et al.  Lipid composition in liver and brain of genetically obese (ob/ob), heterozygote (ob/+)and normal (+/+) mice. , 1982, Biochimica et biophysica acta.

[31]  Clifford B. Saper,et al.  Unraveling the central nervous system pathways underlying responses to leptin , 1998, Nature Neuroscience.

[32]  Thomas C. Südhof,et al.  The synaptic vesicle cycle: a cascade of protein–protein interactions , 1995, Nature.

[33]  E. Nedivi,et al.  A protein associated with axon growth, GAP-43, is widely distributed and developmentally regulated in rat CNS , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[34]  T. T. Yen,et al.  Locomotor Activity of Various Types of Genetically Obese Mice , 1972, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[35]  K. Nakao,et al.  Leptin as a novel placenta-derived hormone in humans , 1998 .

[36]  A. Strosberg,et al.  A leptin missense mutation associated with hypogonadism and morbid obesity , 1998, Nature Genetics.

[37]  C. Mantzoros,et al.  Role of leptin in the neuroendocrine response to fasting , 1996, Nature.

[38]  G. Rebel,et al.  Brain myelin of genetically obese mice , 1985, Journal of the Neurological Sciences.

[39]  R. A. Rajakumar,et al.  Developmental changes in ob gene expression and circulating leptin peptide concentrations. , 1997, Biochemical and biophysical research communications.

[40]  N. Ibarrola,et al.  Hypothyroidism coordinately and transiently affects myelin protein gene expression in most rat brain regions during postnatal development , 1997, Brain Research.

[41]  G. Bray,et al.  Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. , 1979, Physiological reviews.

[42]  T. Noguchi.  Effects of growth hormone on cerebral development: morphological studies. , 1996, Hormone research.

[43]  Aryeh Routtenberg,et al.  GAP-43: an intrinsic determinant of neuronal development and plasticity , 1997, Trends in Neurosciences.

[44]  K. Nakao,et al.  Nonadipose tissue production of leptin: Leptin as a novel placenta-derived hormone in humans , 1997, Nature Medicine.

[45]  T. Horvath,et al.  Leptin Receptor Immunoreactivity is Associated with the Golgi Apparatus of Hypothalamic Neurones and Glial Cells , 1998, Journal of neuroendocrinology.

[46]  F. Bloom,et al.  Opioid peptides and alpha-melanocyte-stimulating hormone in genetically obese (ob/ob) mice during development. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[47]  J. Friedman,et al.  Abnormal regulation of the leptin gene in the pathogenesis of obesity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.