Volume 20, Issue 3, September 2004

Table of Contents 20-3

Leptin Actions on Hypothalamic Neurons & Arcuate Nucleus

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Leptin decreases feeding behavior and encourages weight loss.¹ It stimulates hypothalamic neurons within the arcuate nucleus that synthesize anorexigenic or appetite-suppressing neuropeptides [proopiomelancortin (POMC) and its products -melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript (CART)]. It also suppresses neurons that synthesize orexigenic or appetite-stimulating neurotransmitters [neuropeptide Y (NPY) and agouti-related protein (AgRP)]. These neurons then project to the paraventricular and dorsomedial hypothalamic nuclei, and lateral hypothalamic area (PVH, DMH, LHA, respectively). There, other neuropeptides propagate the feelings of hunger or satiety.² Leptin acts directly upon these neurons through the leptin receptor. Pinto et al identified direct anatomical functional effects of leptin upon these arcuate neurons. They transgenetically programmed wild-type (WT) and ob/ob mice to co-express fluorescent proteins with POMC (topaz) and NPY (sapphire). As expected each neuropeptide was expressed in a different arcuate neuron. They then examined, by patch clamp recordings in arcuate nuclear slices in vitro, the numbers of excitatory and inhibitory afferent inputs into these discrete neurons and quantitated by electron microscopy their anatomically distinct synapses. In ob/ob animals, there were far more excitatory than inhibitory impulses into (and excitatory synapses on) NPY neurons than in WT mice. There were many more inhibitory impulses into (and inhibitory synapses on) POMC neurons in ob/ob than WT mice. Administration of leptin to ob/ob mice reversed these patterns. In WT mice, administration of ghrelin, a gastric appetite-stimulating peptide,^3,4 increased inhibitory and decreased excitatory synapses into/on POMC neurons but did not appear to affect NPY-containing neurons. The authors concluded that there is “neural plasticity” in the arcuate cells containing POMC and NPY and that the effects of leptin and ghrelin are at least partially mediated by such changes.

Bouret et al examined the effect of leptin deprivation and leptin administration upon the density of the neural projections between the arcuate nucleus and the paraventricular nucleus (PVH), dorsomedial hypothalamic nucleus (DMH), and lateral hypothalamic area (LHA) in intact and leptin deficient (ob/ob) mice. They placed a “fluorescent ... tracer that labels axonal projections in fixed tissues” into sections of the arcuate hypothalamic nucleus then examined the pattern of fluorescent projections to the target area(s). In WT animals, the density of these projections increased with age. Relative to WT animals at all ages, leptin deficiency was associated with a greatly decreased number of projections from the arcuate nucleus to all target regions, but not to non-target areas. Administration of leptin to ob/ob adult mice did not alter this pattern. However, leptin given at very high doses intraperitoneally (1 mg/100 mg body weight IP) between postpartum days 4 through 12 restored the density of projections to normal by the 80^th day of life. The authors concluded that leptin is essential for the development of hypothalamic neural pathways that convey leptin downstream signals and that this property was expressed in the neonatal period and perhaps promoted by the neonatal surge in leptin secretion.

Bouret SG, Draper SJ, Simerly RB.Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004;304:108-110.

Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL.Rapid rewiring of arcuate nucleus feeding circuits by leptin.Science 2004 ;304:110-115.

Editor’s Comment: In an accompanying commentary Elmquist and Flier⁴ discussed the significance of the neuroexcitatory and anatomical effects of leptin. They suggested that through the influence of leptin on the excitatory and inhibitory inputs into the arcuate neurons and by stimulation of their neural connectivity, an as yet hypothetical body weight set point might be a functional reality. In mice, there is a surge in leptin secretion in the first week after birth that is not accompanied by a decrease in food intake. The possibility that a body weight set point may be related to and perhaps programmed by the secretion of leptin in the immediate post-partum period (in mice) is intriguing. In human neonates, serum levels of leptin decline over the first 6 days of life and then do not change appreciably over the first 17 days after birth.⁵ Serum leptin concentrations are higher in female than male infants and related to BMI through 12 months of age, but low relative to values in older children and adolescents.^6,7 If there is a set point for body weight as there is for height in man, it is unfortunately easily abridged.

Allen W. Root, MD

References - (linked to )

1. Diamond F. The Endocrine Function of Adlipose Tissue. Growth Genetics Horm 2002;18:17-23.
2. Korner J, Leibel RL. To eat or not to eat - how the gut talks to the brain. N Engl J Med 2003;349:926-928.
3. Casanueva FF, Diequez C. Ghrelin a new hormone implicated in the regulation of growth hormone secretion and body energy homeostasis.Growth Genetics Horm 2004;20:1-8.
4. Elmquist JK, Flier JS. The fat-brain axis enters a new dimension. Science 2004;304:63-64.
5. Matsuda J, Yokota I, Iida M, Murakami T, Yamada M, Saijo T, Naito E, Ito M, Shima K, Kuroda Y. Dynamic changes in serum leptin concentrations during the fetal and neonatal periods. Pediatr Res 1999;45:71-75.
6. Lonnerdal B, Havel PJ. Serum leptin concentrations in infants: effects of diet, sex, and adiposity.
7. Mann DR, Johnson AO, Gimpel T, Castracane VD. Changes in circulating leptin, leptin receptor, and gonadal hormones from infancy until advanced age in humans. J Clin Endocrinol Metab 2003;88:3339-3345.

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