title: A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.
abstract: The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes.
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Reilly
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Sciences, La Jolla, California 92037, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ahmadian
authors.affiliation: Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Zamarron
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Chang
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Maeran
authors.initials: M
authors.lastname: Uhm
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: BreAnne
authors.initials: B
authors.lastname: Poirier
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Peng
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Krause
authors.affiliation: Department of Internal Medicine, Metabolism, Endocrine and Diabetes Division, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Korytnaya
authors.affiliation: Department of Internal Medicine, Metabolism, Endocrine and Diabetes Division, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Neidert
authors.affiliation: 1] Gene Expression Laboratory, Salk Institute for Biological Sciences, La Jolla, California 92037, USA [2] Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Sciences, La Jolla, California 92037, USA.
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Carey N
authors.initials: CN
authors.lastname: Lumeng
authors.affiliation: Department of Internal Medicine, Metabolism, Endocrine and Diabetes Division, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Elif A
authors.initials: EA
authors.lastname: Oral
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Sciences, La Jolla, California 92037, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Sciences, La Jolla, California 92037, USA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D005943:Gluconeogenesis / Q000187:drug effects; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050151:Subcutaneous Fat / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D015850:Interleukin-6; D011943:Receptors, Adrenergic, beta; D050796:STAT3 Transcription Factor; C045742:amlexanox; D000242:Cyclic AMP; D048051:p38 Mitogen-Activated Protein Kinases; D005952:Glucose-6-Phosphatase