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      Signal Transduction Pathways for Leptin : An Embarrassment of Riches

      Diabetes

      American Diabetes Association

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          Abstract

          Leptin is a critical regulator of energy balance in mammals and has served as a launch point for innumerable studies examining the regulation of food intake and energy expenditure (1). At high physiological concentrations, leptin causes a decrease in food intake, an increase in energy expenditure, and a shift to increased fatty acid oxidation. These physiological shifts lead to a decrease in body weight and body fat content. Conversely, a lack of leptin leads to obesity due to hyperphagia and increased lipogenesis. In leptin signaling deficiencies, brown adipose tissue, a major thermogenic organ in small rodents, loses its thermogenic capacity due to diminished sympathetic nervous system activity. In this issue of Diabetes, Rahmouni et al. (2) present a new molecular mechanism by which leptin stimulates anorectic and thermogenic responses in rodents. Given that most of leptin's actions with regard to energy balance occur within the central nervous system, it is currently accepted that a distributed network of leptin receptor–bearing neurons within the hypothalamus are responsible for mediating a concerted response to fluctuations of energy stores within adipose tissue (3). Leptin receptor–bearing neurons are found throughout the hypothalamus, and some of them are chemically defined: arcuate nucleus (proopiomelanocortin [POMC] neurons and agouti-related peptide/neuropeptide Y neurons), ventromedial nucleus (SF1 neurons), and lateral hypothalamus (neurotensin neurons). Other types still must be identified and characterized thoroughly. Analysis of the workings of this distributed network has led to the finding of intriguing and (maddeningly) idiosyncratic properties of the system. For example, leptin is known to cause phosphorylation of signal transducer and elevator of transcription (STAT)3 by the activation of janus kinase (JAK)2 for all cell types studied to date (4). However, leptin causes depolarization of POMC neurons but leads to hyperpolarization of agouti-related peptide/neuropeptide Y neurons (5). This differential response also applies to activation of phosphoinositol-3 kinase (PI3K) within the same two cell types (6). The basis of this differential activation between the two neuronal types remains to be determined. Electrophysiological responses to leptin occur within several minutes, a span of time that is too short to be mediated via transcriptional responses, as would occur with STAT3 activation. Thus, the search for alternative signal transduction pathways for leptin remains an interesting enterprise. Although several traditional signal transduction pathways for leptin were invoked during studies with cultured cells (JAK2-STAT3, Src homology–containing tyrosine phosphatase 2 [Shp2]—extracellular signal–regulated kinase [ERK], and JAK2–phosphoinositol-3 kinase) (6,7), an article in this issue of Diabetes indicates a highly specific role for ERK signaling in leptin's stimulation of anorectic mechanisms and thermogenesis in rodents (1). The authors show that leptin activates ERK signaling specifically in POMC neurons only, greatly simplifying the interpretation of subsequent experiments wherein delivery of ERK pathway inhibitors prevents the anorexia and sympathetic nervous system stimulation of brown adipose tissue after leptin infusion. As ERK is only activated in POMC neurons, the inhibitors are presumably active specifically within POMC neurons. With the plethora of intracellular signal transduction mechanisms that have been shown to be crucial to or involved in mediating leptin's actions, one is in a quandary to assign relative weights to each claim. However, the criterion of necessity for a phenomenon is different from the criterion of sufficiency. Thus, although the authors have shown that ERK signaling is necessary for leptin-induced anorexia, the test of sufficiency has not been applied in this case. Stripped of all other signaling pathways, the test of sufficiency is to determine whether ERK signaling (or any other candidate) solely is responsible for leptin's anorectic and thermogenic responses. It may be necessary to compare the delivery of a cocktail of inhibitors that block all of the known signal transduction mechanisms with a cocktail in which one or more inhibitors has been omitted. Such an experimental paradigm would be useful if all known players have been identified; the same paradigm could also be used to obtain evidence that other unidentified players are involved. Although performing such studies in intact model organisms is challenging, it is the only means to identify the needed components and circuitry for a neuron-mediated response. One particularly complex possibility is that multiple signal transduction pathways are needed for a given physiological response, making the reductionist chase for the sole responsible actor a Sisyphean effort. An important consideration for elucidating the mechanisms of leptin response is the time scale, as mentioned previously. Although immediate responses on a scale of minutes are typically encountered in a neural response, it is well-known that some of leptin's effects are long acting and persistent over several hours. With transcriptional responses, taking into account the hours-long scale for protein products to be synthesized, it is not unreasonable to suggest that some of the responses to leptin might not appear until hours after the initial exposure. The synaptic plasticity of leptin receptor–bearing neurons is one prime example of such a long-lived and persistent response (5). The formation of new synapses could involve prolongation and enhancement of the initial response to leptin, as is seen in the recordings of sympathetic nerve activity after leptin treatment. The next challenge will be to fully examine potential alterations in neuronal circuitry associated with genetic manipulations that could invoke developmental adaptations along with tests of sufficiency for a given intracellular pathway and neural circuit.

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          Most cited references 11

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          Activation of downstream signals by the long form of the leptin receptor.

          The adipocyte-derived hormone leptin signals the status of body energy stores by activating the long form of the leptin receptor (LRb). Activation of LRb results in the activation of the associated Jak2 tyrosine kinase and the transmission of downstream phosphotyrosine-dependent signals. We have investigated the signaling function of mutant LRb intracellular domains under the control of the extracellular erythropoietin (Epo) receptor. By using this system, we confirm that two tyrosine residues in the intracellular domain of murine LRb become phosphorylated to mediate LRb signaling; Tyr(985) controls the tyrosine phosphorylation of SHP-2, and Tyr(1138) controls STAT3 activation. We furthermore investigated the mechanisms by which LRb controls downstream ERK activation and c-fos and SOCS3 message accumulation. Tyr(985)-mediated recruitment of SHP-2 does not alter tyrosine phosphorylation of Jak2 or STAT3 but results in GRB-2 binding to tyrosine-phosphorylated SHP-2 and is required for the majority of ERK activation during LRb signaling. Tyr(985) and ERK activation similarly mediate c-fos mRNA accumulation. In contrast, SOCS3 mRNA accumulation requires Tyr(1138)-mediated STAT3 activation. Thus, the two LRb tyrosine residues that are phosphorylated during receptor activation mediate distinct signaling pathways as follows: SHP-2 binding to Tyr(985) positively regulates the ERK --> c-fos pathway, and STAT3 binding to Tyr(1138) mediates the inhibitory SOCS3 pathway.
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            PI3K integrates the action of insulin and leptin on hypothalamic neurons.

            Central control of energy balance depends on the ability of proopiomelanocortin (POMC) or agouti-related protein (Agrp) hypothalamic neurons to sense and respond to changes in peripheral energy stores. Leptin and insulin have been implicated as circulating indicators of adiposity, but it is not clear how changes in their levels are perceived or integrated by individual neuronal subtypes. We developed mice in which a fluorescent reporter for PI3K activity is targeted to either Agrp or POMC neurons and used 2-photon microscopy to measure dynamic regulation of PI3K by insulin and leptin in brain slices. We show that leptin and insulin act in parallel to stimulate PI3K in POMC neurons but in opposite ways on Agrp neurons. These results suggest a new view of hypothalamic circuitry, in which the effects of leptin and insulin are integrated by anorexigenic but not by orexigenic neurons.
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              Leptin receptor signaling and the regulation of mammalian physiology.

               Logan Myers (2003)
              While the hormone leptin and its receptor were discovered relatively recently, a great deal is already known about the molecular details of leptin receptor (LR) signaling and physiologic regulation. While multiple alternatively spliced LR isoforms exist, only the long (LRb) form associates with the Janus kinase 2 (Jak2) tyrosine kinase to mediate intracellular signaling. LRb initiates signaling via three major mechanisms: 1) Tyr(985) of LRb recruits SH2-containing tyrosine phosphatase (SHP-2); 2) Tyr(1138) of LRb recruits signal transducer and activator of transcription 3 (STAT3); and 3) tyrosine phosphorylation sites on the receptor-associated Jak2 likely recruit numerous undefined signaling proteins. The Tyr(985) --> SHP-2 pathway is a major regulator of extracellular signal-regulated kinase (ERK) activation during leptin signaling in cultured cells, while the Tyr(1138) --> STAT3 pathway induces the feedback inhibitor, suppressor of cytokine signaling 3 (SOCS3), as well as important positive effectors of leptin action. The Jak2-dependent activation of the insulin receptor substrate (IRS) protein --> phosphatidylinositol 3-kinase (PI3'-K) pathway appears to regulate membrane potential in LRb-expressing neurons and contributes to the regulation of feeding. The Tyr(1138) --> STAT3 pathway mediates transcriptional regulation of the hypothalamic melanocortin pathway in vivo. This pathway is required for the regulation of appetite and energy expenditure by leptin. Interestingly, the Tyr(1138) --> STAT3 pathway does not strongly regulate neuropeptide Y (NPY) and thus is not required for the control of reproduction and growth. Thus, other as-yet-undefined leptin receptor signals are central to these and perhaps other aspects of leptin action.
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                Author and article information

                Affiliations
                From the Departments of Medicine and Neuroscience, Albert Einstein College of Medicine, Bronx, New York
                Author notes

                Corresponding author: Streamson Chua, Jr., schua@123456aecom.yu.edu

                Journal
                Diabetes
                diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                March 2009
                : 58
                : 3
                : 513-514
                2646045
                19246598
                583513
                10.2337/db08-1646
                Copyright © 2009, American Diabetes Association

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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