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      Ablation of LMO4 in glutamatergic neurons impairs leptin control of fat metabolism

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          Abstract

          The LIM domain only 4 (LMO4) protein is expressed in the hypothalamus, but its function there is not known. Using mice with LMO4 ablated in postnatal glutamatergic neurons, including most neurons of the paraventricular (PVN) and ventromedial (VMH) hypothalamic nuclei where LMO4 is expressed, we asked whether LMO4 is required for metabolic homeostasis. LMO4 mutant mice exhibited early onset adiposity. These mice had reduced energy expenditure and impaired thermogenesis together with reduced sympathetic outflow to adipose tissues. The peptide hormone leptin, produced from adipocytes, activates Jak/Stat3 signaling at the hypothalamus to control food intake, energy expenditure, and fat metabolism. Intracerebroventricular infusion of leptin suppressed feeding similarly in LMO4 mutant and control mice. However, leptin-induced fat loss was impaired and activation of Stat3 in the VMH was blunted in these mice. Thus, our study identifies LMO4 as a novel modulator of leptin function in selective hypothalamic nuclei to regulate fat metabolism.

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          Coordinated transcription of key pathways in the mouse by the circadian clock.

          Satchidananda Panda, Marina P. Antoch, Brooke H. Miller … (2002)
          In mammals, circadian control of physiology and behavior is driven by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. We have used gene expression profiling to identify cycling transcripts in the SCN and in the liver. Our analysis revealed approximately 650 cycling transcripts and showed that the majority of these were specific to either the SCN or the liver. Genetic and genomic analysis suggests that a relatively small number of output genes are directly regulated by core oscillator components. Major processes regulated by the SCN and liver were found to be under circadian regulation. Importantly, rate-limiting steps in these various pathways were key sites of circadian control, highlighting the fundamental role that circadian clocks play in cellular and organismal physiology.
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            The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis.

            Daniela Cota, Giovanni Marsicano, Matthias Tschöp … (2003)
            The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1-/-) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1-/- mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1-/- mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity, body temperature, or energy expenditure. Hypothalamic CB1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and preproorexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1-/- mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced lipogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.
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              Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.

              C Bjørbaek, D D Pierroz, Barbara M Hileman … (2000)
              Obesity in humans and in rodents is usually associated with high circulating leptin levels and leptin resistance. To examine the molecular basis for leptin resistance, we determined the ability of leptin to induce hypothalamic STAT3 (signal transducer and activator of transcription) signaling in C57BL/6J mice fed either low-fat or high-fat diets. In mice fed the low-fat diet, leptin activated STAT3 signaling when administered via the intraperitoneal (ip) or the intracerebroventricular (icv) route, with the half-maximal dose being 30-fold less when given by the icv route. The high-fat diet increased body-weight gain and plasma leptin levels. After 4 weeks on the diet, hypothalamic STAT3 signaling after ip leptin administration was equivalent in both diet groups. In contrast, peripherally administered leptin was completely unable to activate hypothalamic STAT3 signaling, as measured by gel shift assay after 15 weeks of high-fat diet. Despite the absence of detectable signaling after peripheral leptin at 15 weeks, the mice fed the high-fat diet retained the capacity to respond to icv leptin, although the magnitude of STAT3 activation was substantially reduced. These results suggest that leptin resistance induced by a high-fat diet evolves during the course of the diet and has at least two independent causes: an apparent defect in access to sites of action in the hypothalamus that markedly limits the ability of peripheral leptin to activate hypothalamic STAT signaling, and an intracellular signaling defect in leptin-responsive hypothalamic neurons that lies upstream of STAT3 activation.
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                Author and article information

                Contributors
                : +1-613-5625800 , +1-613-5625403 , hchen@uottawa.ca
                Journal
                Journal ID (nlm-ta): Cell Mol Life Sci
                Title: Cellular and Molecular Life Sciences
                Publisher: SP Birkhäuser Verlag Basel (Basel )
                ISSN (Print): 1420-682X
                ISSN (Electronic): 1420-9071
                Publication date (Electronic): 27 August 2011
                Publication date PMC-release: 27 August 2011
                Publication date (Print): March 2012
                Volume: 69
                Issue: 5
                Pages: 819-828
                Affiliations
                [1 ]Centre for Stroke Recovery, Neuroscience, Ottawa Health Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5 Canada
                [2 ]Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
                [3 ]Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada
                [4 ]Department of Medicine, University of Ottawa, Ottawa, ON K1H 8M5 Canada
                [5 ]Institute of Neuroscience, Carleton University, Ottawa, ON K1S 5B6 Canada
                Article
                Publisher ID: 794
                DOI: 10.1007/s00018-011-0794-3
                PMC ID: 3276759
                PubMed ID: 21874351
                SO-VID: a4f35a1a-a545-47da-bcb1-ae562bc09dbe
                Copyright © © The Author(s) 2011
                History
                Date received : 26 May 2011
                Date revision received : 8 July 2011
                Date accepted : 8 August 2011
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © Springer Basel AG 2012

                ScienceOpen disciplines: Molecular biology
                Keywords: leptin,hypothalamus,sympathetic outflow,obesity,adiposity
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: leptin, hypothalamus, sympathetic outflow, obesity, adiposity

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