Novel Leptin-Regulated Genes Revealed by Transcriptional Profiling of the Hypothalamic Paraventricular Nucleus

Tung, Yi-Chun Loraine; Ma, Marcella; Piper, Sarah; Coll, Anthony P.; O’Rahilly, Stephen; Yeo, Giles S.H.

doi:10.1523/jneurosci.3412-08.2008

Cited by 108 publications

(104 citation statements)

References 48 publications

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“…Expression of oxytocin mRNA is known to be regulated by feeding/fasting (Kublaoui et al, 2008;Tung et al, 2008). We examined whether the association of PGC-1␣ with the oxtl promoter is correlated with nutrient regulation of oxytocin mRNA in adult zebrafish.…”

Section: Resultsmentioning

confidence: 99%

The Metabolic Regulator PGC-1α Directly Controls the Expression of the Hypothalamic Neuropeptide Oxytocin

Blechman¹,

Amir-Zilberstein²,

Gutnick³

et al. 2011

J. Neurosci.

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The transcriptional coactivator PGC-1␣ is a key regulator of cellular energy expenditure in peripheral tissues. Recent studies report that PGC-1␣-null mice develop late-onset obesity and that the neuronal inactivation of PGC-1␣ causes increased food intake. However, the exact role of PGC-1␣ in the CNS remains unclear. Here we show that PGC-1␣ directly regulates the expression of the hypothalamic neuropeptide oxytocin, a known central regulator of appetite. We developed a unique genetic approach in the zebrafish, allowing us to monitor and manipulate PGC-1␣ activity in oxytocinergic neurons. We found that PGC-1␣ is coexpressed with oxytocin in the zebrafish hypothalamus. Targeted knockdown of the zebrafish PGC-1␣ gene activity caused a marked decrease in oxytocin mRNA levels and inhibited the expression of a transgenic GFP reporter driven by the oxytocin promoter. The effect of PGC-1␣ loss of function on oxytocin gene activity was rescued by tissue-specific re-expression of either PGC-1␣ or oxytocin precursor in zebrafish oxytocinergic neurons. PGC-1␣ activated the oxytocin promoter in a heterologous cell culture system, and overexpression of PGC-1␣ induced ectopic expression of oxytocin in muscles and neurons. Finally, PGC-1␣ forms an in vivo complex with the oxytocin promoter in fed but not fasted animals. These findings demonstrate that PGC-1␣ is both necessary and sufficient for the production of oxytocin, implicating hypothalamic PGC-1␣ in the direct activation of a hypothalamic hormone known to control energy intake.

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Section: Resultsmentioning

confidence: 99%

The Metabolic Regulator PGC-1α Directly Controls the Expression of the Hypothalamic Neuropeptide Oxytocin

Blechman¹,

Amir-Zilberstein²,

Gutnick³

et al. 2011

J. Neurosci.

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“…The microarray data obtained were analyzed maintaining high stringency in order to reduce the number of false positives, as previously reported (Tung et al 2008). Three different analysis algorithms were used: (1) GeneChip Operating Software (GCOS), (2) Robust Multiarray Average (RMA), and (3) a variant of RMA that uses probe sequence coupled with GC-content background correction (GC-RMA).…”

Section: Microarray Analysis Of Embryonic and Adult Drg Axonal Mrnasmentioning

confidence: 99%

Transcriptome analysis of embryonic and adult sensory axons reveals changes in mRNA repertoire localization

Gumy¹,

Yeo²,

Tung³

et al. 2010

RNA

334

401

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mRNAs are transported, localized, and translated in axons of sensory neurons. However, little is known about the full repertoire of transcripts present in embryonic and adult sensory axons and how this pool of mRNAs dynamically changes during development. Here, we used a compartmentalized chamber to isolate mRNA from pure embryonic and adult sensory axons devoid of non-neuronal or cell body contamination. Genome-wide microarray analysis reveals that a previously unappreciated number of transcripts are localized in sensory axons and that this repertoire changes during development toward adulthood. Embryonic axons are enriched in transcripts encoding cytoskeletal-related proteins with a role in axonal outgrowth. Surprisingly, adult axons are enriched in mRNAs encoding immune molecules with a role in nociception. Additionally, we show Tubulin-beta3 (Tubb3) mRNA is present only in embryonic axons, with Tubb3 locally synthesized in axons of embryonic, but not adult neurons where it is transported, thus validating our experimental approach. In summary, we provide the first complete catalog of embryonic and adult sensory axonal mRNAs. In addition we show that this pool of axonal mRNAs dynamically changes during development. These data provide an important resource for studies on the role of local protein synthesis in axon regeneration and nociception during neuronal development.

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“…Upon hLeptin-antibody fusion treatment, expression of SOCS3 is significantly up-regulated in the hypothalamus. Ndufa8 is a marker gene for the leptin-regulated mitochondrial oxidative phosphorylation (OXPHOS) pathway, which is significantly overrepresented in brain (48). We found that Ndufa8 was up-regulated in hypothalamus upon hLeptin-Herceptin treatment, whereas no significant difference was observed in liver.…”

Section: Resultsmentioning

confidence: 78%

“…We therefore analyzed whether hLeptin-CDR3H-coil-Herceptin up-regulated gene expression in liver and hypothalamus at multiple time points by quantitative PCR in mice treated with the fusion protein ( Table 2). Three representative organ-specific leptin-regulated genes were selected, which include Glucokinase (GCK) (47), NADH dehydrogenase (ubiquinone) 1 α subcomplex (Ndufa8) (48), and cytokine signaling 3 (SOCS3) (49). GCK is a ubiquitously expressed, key metabolic gene with strong responsiveness to hLeptin.…”

Section: Resultsmentioning

confidence: 99%

Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists

Liu

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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On the basis of the 3D structure of a bovine antibody with a wellfolded, ultralong complementarity-determining region (CDR), we have developed a versatile approach for generating human or humanized antibody agonists with excellent pharmacological properties. Using human growth hormone (hGH) and human leptin (hLeptin) as model proteins, we have demonstrated that functional human antibody CDR fusions can be efficiently engineered by grafting the native hormones into different CDRs of the humanized antibody Herceptin. The resulting Herceptin CDR fusion proteins were expressed in good yields in mammalian cells and retain comparable in vitro biological activity to the native hormones. Pharmacological studies in rodents indicated a 20-to 100-fold increase in plasma circulating half-life for these antibody agonists and significantly extended in vivo activities in the GH-deficient rat model and leptin-deficient obese mouse model for the hGH and hLeptin antibody fusions, respectively. These results illustrate the utility of antibody CDR fusions as a general and versatile strategy for generating long-acting protein therapeutics.antibody | protein engineering | growth hormone | leptin | pharmacology M any endocrine hormones are used therapeutically (1); however, they generally suffer from short circulating halflives (2, 3) and therefore require high doses and frequent injections to achieve efficacious exposures. For example, human growth hormone (hGH) is a 22-kDa four-helix-bundle protein produced by the pituitary gland, and its recombinant form has long been used for the treatment of growth hormone deficiency (GHD). Due to the short in vivo half-life of hGH, which is on the timescale of minutes, current GHD therapy requires daily injection (4), resulting in lower patient compliance (5). Studies have shown that a continuous infusion of recombinant (r)hGH has a similar efficacy and safety profile as daily rhGH therapy (6), and thus there is considerable interest in the development of long-acting forms of hGH. The first and only approved long-acting hGH, Nutropin Depot, a sustained-release formulation based on a biodegradable polymer, was withdrawn due to manufacturing difficulties. Various forms of long-acting GH have since been generated: those currently in clinical development include LB03002 (microparticle suspension), NNC126-0083 (PEGylation), NNC0195-0092 (reversible albumin-binding GH derivative), MOD-4023 (CTP modification), ACP-001 (prodrug strategy), Albutropin (albumin fusion), and VRS-317 (XTEN fusion), and have been extensively reviewed elsewhere (5). However, challenges associated with heterogeneity, stability, immunogenicity, toxicity, and/or compromised potency could potentially limit their clinical utility (3, 7-10).Another short-lived hormone in which there is considerable clinical interest is human leptin, a 16-kDa four-helix-bundle protein that plays a central role in the homeostasis of body weight. Recombinant leptin has been approved for the treatment of leptindeficient lipodystrophy patients (11), and ...

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Novel Leptin-Regulated Genes Revealed by Transcriptional Profiling of the Hypothalamic Paraventricular Nucleus

Cited by 108 publications

References 48 publications

The Metabolic Regulator PGC-1α Directly Controls the Expression of the Hypothalamic Neuropeptide Oxytocin

The Metabolic Regulator PGC-1α Directly Controls the Expression of the Hypothalamic Neuropeptide Oxytocin

Transcriptome analysis of embryonic and adult sensory axons reveals changes in mRNA repertoire localization

Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists

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