Adipokine Gene Expression in a Novel Hypothalamic Neuronal Cell Line: Resistin-Dependent Regulation of Fasting-Induced Adipose Factor and SOCS-3
Department of Obstetrics, Faculty of Medicine, Dalhousie University, Halifax, N.S., Canada. Neuroendocrinology
(Impact Factor: 4.37).
02/2007; 85(4):232-41. DOI: 10.1159/000104248
Adipokines such as leptin, resistin, and fasting-induced adipose factor (FIAF) are secreted by adipocytes, but their expression is also detectable in the brain and pituitary. The role of central adipokines remains elusive, but we speculate that they may modulate those hypothalamic signaling pathways that control energy homeostasis. Here we describe experiments to test this in which we exploited a novel hypothalamic neuronal cell line (N-1) that expresses a variety of neuropeptides and receptors that are known to be implicated in appetite regulation. Using real-time RT-PCR, we confirmed that N-1 neurons express resistin (rstn) and fiaf, as well as suppressor of cytokine signaling-3 (socs-3), a feedback inhibitor of leptin signaling. Treating N-1 cells with recombinant resistin (200 ng/ml, 30 min) reduced both fiaf (25%, p socs-3 (29%, p fiaf (40%, p socs-3 (25%, p rstn levels (–60%, p fiaf and socs-3 expression was increased (46 and 65% respectively, p rstn mRNA was achieved using RNAi in differentiated 3T3-L1 adipocytes, and this manipulation also reduced fiaf and socs-3 expression (–53, –21 and –20% respectively, p fiaf mRNA by 50% (p rstn or socs-3 mRNA. These data suggest that resistin exerts a novel autocrine/paracrine control over fiaf and socs-3 expression in both 3T3-L1 adipocytes and N-1 neurons. Such a mechanism could be part of the central feedback system that modulates the effects of adipokines, and other adiposity signals, implicated in hypothalamic energy homeostasis. However, it remains to be determined whether these in vitro results can be translated to the control of adipokine expression in brain and adipose tissue.
Figures in this publication
Available from: Yael Kuperman
- "We found that N42 cells express TLR2 (Fig. 6A), and respond to their well known pharmacological activators (the lipopeptide, Pam3CysSK4 (P3C), and peptidoglycan (PG)), as manifested by increased c-Fos expression, an established indicator of recent neuronal activity (Fig. 6B,C). To evaluate whether such TLR2 activation by the hypothalamic neurons would lead to metabolic consequences, we tested the effect of the TLR2 ligands on the expression of resistin (rstn) and fasting-induced adipose factor (fiaf; also known as angiopoietin-like 4), adipokines that have been previously shown to be regulated in this cell line and expressed in the brain, where they modulate hypothalamic signaling pathways and control energy homeostasis30. Administration of the TLR2 ligands, resulted in reduced mRNA transcript levels of resistin (Fig. 6D), a phenomenon previously linked to an increase in POMC and α-MSH, and known to induce an anorectic response mediated at the hypothalamus30. "
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ABSTRACT: Toll-like receptors (TLRs) are traditionally associated with immune-mediated host defense. Here, we ascribe a novel extra-immune, hypothalamic-associated function to TLR2, a TLR-family member known to recognize lipid components, in the protection against obesity. We found that TLR2-deficient mice exhibited mature-onset obesity and susceptibility to high-fat diet (HFD)-induced weight gain, via modulation of food intake. Age-related obesity was still evident in chimeric mice, carrying comparable TLR2(+) immune cells, suggesting a non-hematopoietic-related involvement of this receptor. TLR2 was up-regulated with age or HFD in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus, a brain area participating in central-metabolic regulation, possibly modulating the hypothalamic-anorexigenic peptide, α-melanocyte-stimulating hormone (α-MSH). Direct activation of TLR2 in a hypothalamic-neuronal cell-line via its known ligands, further supports its capacity to mediate non-immune related metabolic regulation. Thus, our findings identify TLR2 expressed by hypothalamic neurons as a potential novel regulator of age-related weight gain and energy expenditure.
Available from: Valerie Bracchi-Ricard
- "It has been established that the adipokine leptin governs physiological effects on energy homeostasis through hypothalamic pathways mediated by its cognate long form receptor (LepRb) , –. LepRb initiates Jak2/Stat3 signaling pathways in subpopulations of neurons in the arcuate nucleus (ARC) of the hypothalamus, activating the transcription of the precursor poly-peptide proopiomelanocortin (POMC) which in turn triggers neuro-endocrine pathways associated with metabolic rate, mobilization of energy stores as well as many other growth related processes –. "
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ABSTRACT: Chronic spinal cord injury (SCI) results in an accelerated trajectory of several cardiovascular disease (CVD) risk factors and related aging characteristics, however the molecular mechanisms that are activated have not been explored. Adipokines and leptin signaling are known to play a critical role in neuro-endocrine regulation of energy metabolism, and are now implicated in central inflammatory processes associated with CVD. Here, we examine hypothalamic adipokine gene expression and leptin signaling in response to chronic spinal cord injury and with advanced age. We demonstrate significant changes in fasting-induced adipose factor (FIAF), resistin (Rstn), long-form leptin receptor (LepRb) and suppressor of cytokine-3 (SOCS3) gene expression following chronic SCI and with advanced age. LepRb and Jak2/stat3 signaling is significantly decreased and the leptin signaling inhibitor SOCS3 is significantly elevated with chronic SCI and advanced age. In addition, we investigate endoplasmic reticulum (ER) stress and activation of the uncoupled protein response (UPR) as a biological hallmark of leptin resistance. We observe the activation of the ER stress/UPR proteins IRE1, PERK, and eIF2alpha, demonstrating leptin resistance in chronic SCI and with advanced age. These findings provide evidence for adipokine-mediated inflammatory responses and leptin resistance as contributing to neuro-endocrine dysfunction and CVD risk following SCI and with advanced age. Understanding the underlying mechanisms contributing to SCI and age related CVD may provide insight that will help direct specific therapeutic interventions.
Available from: PubMed Central
- "These cells were chosen since they were derived from the embryonic mouse hypothalamus and express a range of neuropeptides involved in normal hypothalamic function and metabolism. Although fiaf expression was significantly reduced using a chemically modified small interfering RNA (siRNA), this failed to significantly modify the expression of other genes being analysed (60). In marked contrast, the RNAi-mediated silencing of rstn induced significant increases (>50%) in both fiaf and suppressor of cytokine signaling-3 (socs-3) when N-1 cells were cultured in serum-deprived medium (60). "
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ABSTRACT: Obesity is one of the most prevalent medical conditions, often associated with several negative stereotypes. Although it is true that weight gain occurs when food intake exceeds energy expenditure, it is important to note that even a 1% mismatch between the two can lead to a substantial weight gain after only a few years. Further, the body appears to balance energy metabolism via an endogenous lipostatic loop in which adipose stores send hormonal signals (e.g. adipokines such as leptin) to the hypothalamus in order to reduce appetite and increase energy expenditure. However, the brain is also a novel site of expression of many of these adipokine genes. This led to the hypothesis that hypothalamic-derived adipokines might also be involved in bodyweight regulation by exerting some effect on the control of appetite or hypothalamic function. When RNA interference (RNAi) was used to specifically silence adipokine gene expression in various in vitro models, this led to increases in cell death, modification of the expression of key signaling genes (i.e. suppressor of cytokine signaling-3; SOCS-3), and modulation of the activation of cellular energy sensors (i.e. adenosine monophosphate-activated protein kinase; AMPK). Subsequently, when RNAi was used to inhibit the expression of brain-derived leptin in adult rats this resulted in minor increases in weight gain in addition to modifying the expression of other adipokine genes (eg. resistin). In summary, although adipokines secreted by adipose tissue appear to the main regulator of lipostatic loop, this review shows that the fine tuning that is required to maintain a stable bodyweight by this system might be accomplished by hypothalamic-derived adipokines. Perturbations in this central adipokine system could lead to alterations in normal hypothalamic function which leads to unintended weight gain.
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