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ScienceWeek
NEUROBIOLOGY: ON LEPTIN AND THE BRAIN
The following points are made by J.K. Elmquist and J.S. Flier (Science 2004 304:63):
1) The year 2004 marks the end of the first decade of research on leptin (1). The discovery of this hormone, which is produced by fat cells (adipocytes) and suppresses appetite, dramatically accelerated the pace of research on obesity, the neurobiology of feeding, and diabetes. The ensuing research produced a preliminary roadmap of the central nervous system (CNS) circuitry through which key metabolic signals like leptin exert their effects (2-4).
2) Remarkably, new actions for this hormone continue to be identified. Pinto et al (5) and Bouret et al (Science 2004 304:108)) have extended substantially the breadth of leptin's neurobiological actions within the CNS. These reports suggest that leptin is a crucial regulator of both synaptic plasticity and axon guidance within the hypothalamus. Although much remains to be learned, these studies reveal fresh links between nutrition and neurodevelopment mediated by this adipocyte-derived hormone, with potentially important implications for the physiology of energy balance and body weight homeostasis.
3) Pinto et al (5) assessed the acute effects of leptin on synaptic plasticity in the arcuate nucleus of the hypothalamus. The arcuate nucleus is one of the key targets of circulating hormones such as leptin. At least two distinct populations of neurons with opposing actions on food intake reside in the arcuate nucleus. The first population produces the "orexigenic" (appetite-stimulating) neuropeptides NPY and AgRP (neuropeptide Y and agouti-related protein). The second population produces the "anorexigenic" (appetite-suppressing) neuropeptides POMC and CART (proopiomelanocortin and cocaine- and amphetamine-regulated transcript). Both populations of neurons express leptin receptors, and are regulated by leptin in opposite ways. Leptin activates the POMC/CART neurons directly but blocks the activity of the NPY/AgRP neurons (2-4). To add to the complexity, NPY/AgRP neurons produce the inhibitory neurotransmitter GABA and send collateral inputs to the POMC/CART neurons that may chronically inhibit these neurons.
4) Pinto et al (5) add to the complexity of this system by reporting that in a leptin-deficient state, the excitatory and inhibitory synaptic inputs to the POMC and NPY neurons are markedly altered. Using leptin-deficient (ob/ob) mice expressing variants of green fluorescent protein in POMC and NPY neurons, they assessed the electrophysiological properties of both cell groups. They found that a leptin deficiency in the ob/ob mice caused an increase in the excitatory inputs (EPSCs) to the orexigenic NPY/AgRP neurons and a parallel increase in the inhibitory inputs to the anorexigenic POMC/CART neurons. These changes in electrophysiological activity were accompanied by altered numbers of excitatory and inhibitory synapses observed at the ultrastructural level. Thus, lack of leptin increased excitatory inputs (presumably glutamatergic synapses) on NPY/AgRP neurons and decreased excitatory synaptic inputs to POMC neurons. Importantly, leptin repletion in ob/ob mice reversed these effects, both at the electrophysiological and ultrastructural levels.
References (abridged):
1. Y. Zhang et al., Nature 372, 425 (1994)
2. J. S. Flier, Cell 116, 337 (2004)
3. J. M. Zigman, J. K. Elmquist, Endocrinology 144, 3749 (2003)
4. C. B. Saper, T. C. Chou, J. K. Elmquist, Neuron 36, 199 (2002)
5. S. Pinto et al., Science 304, 110 (2004)
Science http://www.sciencemag.org
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Related Material:
ON LEPTIN AND THE REGULATION OF MAMMALIAN BODY WEIGHT
Notes by ScienceWeek:
The assimilation, storage, and use of energy from nutrients constitute a *homeostatic system essential for life. In vertebrates, the ability to store sufficient quantities of energy-dense triglycerides in *adipose tissue allows survival during periods of food deprivation. However, the presence of excess adipose tissue can be evolutionary maladaptive, and a complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level.
Leptin is a hormone secreted by adipose tissue, and this hormone and its receptor are apparently integral components of the fuel-energy regulatory system. Leptin also apparently signals nutritional status to several other physiological systems and modulates their function.
The following points are made by J.M. Friedman and J.L. Halaas (Nature 1998 395:763):
1) The belief that obesity is largely the result of a lack of willpower, though widely held, is unsatisfactory. Studies of twins, analyses of *familial aggregation, adoption studies, and animal models of obesity all indicate that obesity is the result of both genetic and environmental factors. Moreover, weight is stable in lean and obese individuals even though much of the population actively practices weight control. Dieting is not usually successful in long-term maintenance of reduced body weight, and most reduced obese individuals eventually regain the lost weight.
2) *Recessive mutations in the mouse and genes result in obesity and diabetes in a syndrome resembling pathological human obesity... The *cloning and characterization of the gene has indicated that it encodes a hormone, leptin (from the Greek leptos = thin), that is expressed in adipose tissue and, at lower levels, in *gastric epithelium and *placenta.
3) Early data indicated that leptin might be an *afferent signal in a negative-feedback loop regulating the size of adipose tissue mass... The *plasma levels of leptin are highly correlated with adipose tissue mass and fall in both humans and mice after weight loss. Levels of leptin are increased in obese humans and in several genetic and environmentally induced forms of rodent obesity.
4) The role of leptin in the pathogenesis of obesity can be inferred by measurement of plasma leptin. An increase in plasma leptin suggests that obesity is the result of resistance to leptin (e.g., a dysfunction that reduces the effectiveness of leptin as a signal messenger). A low or normal plasma concentration of leptin in the context of obesity suggests decreased production of leptin. This interpretation is similar to that used in studies of *insulin and the pathogenesis of *type I and type II diabetes.
5) The possible therapeutic benefits of leptin treatment in humans is now being studied in clinical trials, and early data indicate that 4 weeks of daily leptin injections are safe and cause small but significant weight loss in lean and obese subjects compared with placebo effects. A subset of 8 obese subjects treated for a total of 6 months lost an average of 7.1 kilograms compared with 1.7 kilograms in a group receiving placebo. Some of the obese subjects lost substantial amounts of weight but others did not... This limited study indicates that leptin might be an effective therapy for some obese subjects, although more patients need to be investigated.
6) The authors conclude: Whether leptin finds its way into general usage as an anti-obesity drug, the use of modern methods to identify and target the components of the leptin signalling pathway will form the basis for new pharmacological approaches to the treatment of obesity and other nutritional disorders. Further studies of leptin are also likely to reveal additional links between nutritional state and animal physiology.
Nature http://www.nature.com/nature
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Notes by ScienceWeek:
homeostatic system: The term "homeostasis" refers to a physiological equilibrium necessary in general for the viability of an organism, and in particular for the operation of many cellular functions. Homeostatic mechanisms in biological systems usually involve an element of negative feedback signaling. In vertebrates, for example, when blood temperature is too high, temperature receptors provoke a sequence of events involving many pathways that ultimately results in a lowering of body temperature. Similar homeostatic mechanisms operate at cellular levels.
adipose tissue: Connective tissue consisting chiefly of fat cells, which are cells distended with one or more fat globules, the cytoplasm usually compressed into a thin envelope. Fat cells are also called "adipocytes".
familial aggregation: This refers to the occurrence of a trait in more members of a family than can be readily accounted for by chance -- i.e., presumptive but not cogent evidence of the operation of genetic factors.
Recessive mutations: A variant of a particular gene that fails to be expressed except when occurring in both alleles of the gene.
cloning: In general, the term "cloning" has two meanings. 1) With reference to cells, cloning is any process by which a line of identical cells is produced from one or a few originating cells. 2) With reference to DNA, cloning is any process by which a gene or fragment of DNA is spliced into a *vector so that the DNA can be amplified many times by transferring the recombinant (i.e., foreign) DNA molecule into a host organism (usually a bacterium or yeast) that can be grown in large quantities.
vector: In this context, a vector is any DNA that can propagate itself rapidly in a host cell and maintain this capability after insertion of foreign DNA into the vector. For example, one can introduce a human DNA fragment (e.g., a gene) into the DNA of a virus, have this virus infect its usual host cells (e.g., bacteria or animal cells), and if the virus is rapidly replicating, the fragment of human DNA will also be rapidly replicated. The procedure, in other words, uses viral DNA as a means (a vector) to introduce the foreign DNA (here a human DNA fragment incorporated into the viral DNA) into a host cell to use the host cell-virus system as a chemical factory to produce relatively large quantities of the foreign DNA fragment.
gastric epithelium: In animals, epithelial cells (epithelium) compose the cell layers that form the interface between a tissue and the external environment, for example, the cells of the skin, the lining of the intestinal tract, and the lung airway passages. "Gastric epithelium" is epithelium of the gastrointestinal tract.
placenta: In general, the organ of metabolic interchange between the fetus and the mother.
afferent signal: In general, an "afferent" signal in physiology is a signal *to* a control center, and an "efferent" signal in physiology is a signal *from* a control center.
plasma levels: In general, the noncellular portion of circulating blood.
insulin: A polypeptide hormone that promotes uptake by body cells of free glucose and/or amino acids, depending on target cell type.
type I and type II diabetes: (type I and type II diabetes mellitus) Diabetes is a metabolic disease in which carbohydrate utilization is reduced and that of lipid and protein enhanced. The disease is caused by an absolute or relative deficiency of insulin. There are many forms of diabetes, with primary (essential) diabetes comprising two types: type I diabetes is insulin-dependent, requiring chronic insulin treatment, and usually occurring before age 30; type II diabetes is non-insulin-dependent, usually occurs after age 30, and is the diabetes type commonly associated with obesity. In the US there are 14 million known cases of diabetes, and approximately 90 percent of these are type II.
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