title: Shc depletion stimulates brown fat activity in vivo and in vitro.
abstract: Adipose tissue is an important metabolic organ that integrates a wide array of homeostatic processes and is crucial for whole-body insulin sensitivity and energy metabolism. Brown adipose tissue (BAT) is a key thermogenic tissue with a well-established role in energy expenditure. BAT dissipates energy and protects against both hypothermia and obesity. Thus, BAT stimulation therapy is a rational strategy for the looming pandemic of obesity, whose consequences and comorbidities have a huge impact on the aged. Shc-deficient mice (ShcKO) were previously shown to be lean, insulin sensitive, and resistant to high-fat diet and obesity. We investigated the contribution of BAT to this phenotype. Insulin-dependent BAT glucose uptake was higher in ShcKO mice. Primary ShcKO BAT cells exhibited increased mitochondrial respiration; increased expression of several mitochondrial and lipid-oxidative enzymes was observed in ShcKO BAT. Levels of brown fat-specific markers of differentiation, UCP1, PRDM16, ELOVL3, and Cox8b, were higher in ShcKO BAT. In vitro, Shc knockdown in BAT cell line increased insulin sensitivity and metabolic activity. In vivo, pharmacological stimulation of ShcKO BAT resulted in higher energy expenditure. Conversely, pharmacological inhibition of BAT abolished the improved metabolic parameters, that is the increased insulin sensitivity and glucose tolerance of ShcKO mice. Similarly, in vitro Shc knockdown in BAT cell lines increased their expression of UCP1 and metabolic activity. These data suggest increased BAT activity significantly contributes to the improved metabolic phenotype of ShcKO mice.
authors.affiliation: Department of Molecular Biosciences, UC Davis, Davis, CA, 95616, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Tomilov
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bettaieb
authors.forename: Kyoungmi
authors.initials: K
authors.lastname: Kim
authors.forename: Sunil
authors.initials: S
authors.lastname: Sahdeo
authors.forename: Natalia
authors.initials: N
authors.lastname: Tomilova
authors.forename: Adam
authors.initials: A
authors.lastname: Lam
authors.forename: Kevork
authors.initials: K
authors.lastname: Hagopian
authors.forename: Michelle
authors.initials: M
authors.lastname: Connell
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fong
authors.forename: Douglas
authors.initials: D
authors.lastname: Rowland
authors.forename: Stephen
authors.initials: S
authors.lastname: Griffey
authors.forename: Jon
authors.initials: J
authors.lastname: Ramsey
authors.forename: Fawaz
authors.initials: F
authors.lastname: Haj
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism; D051379:Mice; D018345:Mice, Knockout; D055765:Shc Signaling Adaptor Proteins / Q000172:deficiency* / Q000378:metabolism*; D022722:Thermogenesis / Q000502:physiology
chemical_list: D055765:Shc Signaling Adaptor Proteins
keywords: Shc; brown adipose; brown adipose tissue; energy expenditure; healthy aging; insulin