title: A novel role of the checkpoint kinase ATR in leptin signaling.
abstract: In a world with increasing incidences of obesity, it becomes critical to understand the detailed regulation of appetite. To identify novel regulators of the signaling mediated by one of the key hormones of energy homeostasis, leptin, we screened a set of compounds for their effect on the downstream Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Interestingly, cells exposed to inhibitors of the Ataxia Telangiectasia and RAD3-related protein ATR increased their leptin dependent STAT3 activity. This was due to failure of the cells to induce the negative feedback mediator Suppressor of Cytokine Signaling 3 (SOCS3), suggesting that ATR has a previously unknown role in the negative feedback regulation of leptin signaling. This is an important finding not only because it sheds light on additional genes involved in leptin signaling, but also because it brings forward a new potential therapeutic intervention point for increasing leptin signaling in obese individuals.
authors.affiliation: Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Pepparedsleden 1, 431 83 Mölndal, Sweden. Electronic address: Elke.Ericson@astrazeneca.com.
authors.forename: Elke
authors.initials: E
authors.lastname: Ericson
authors.affiliation: Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Pepparedsleden 1, 431 83 Mölndal, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Wennberg Huldt
authors.affiliation: Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Pepparedsleden 1, 431 83 Mölndal, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Strömstedt
authors.affiliation: Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Pepparedsleden 1, 431 83 Mölndal, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Brodin
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology; D025461:Feedback, Physiological; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D020738:Leptin / Q000502:physiology*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020738:Leptin; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: Ataxia Telangiectasia and RAD3 related protein; Leptin; Signal Transducer and Activator of Transcription 3 protein; Suppressor of Cytokine Signaling 3