Abstract
SummaryObesity has become an explicit public health concern because of its relevance to metabolic syndrome. Evidence points to the significance of beige adipocytes in regulating energy expenditure. Here, using yeast two-hybrid screening, we show that Zfp238 is a Foxo1 co-repressor and that adipose-tissue-specific ablation of Zfp238 (Adipo-Zfp238KO) in mice leads to obesity, decreased energy expenditure, and insulin resistance under normal chow diet. Adipo-Zfp238KO inhibits induction of Ucp1 expression in subcutaneous adipose tissue upon cold exposure or CL316243, but not in brown adipose tissue. Furthermore, knockdown of Zfp238 in 3T3-L1 cells decreases Ucp1 expression in response to cool incubation or forskolin significantly compared with control cells. In contrast, overexpression of Zfp238 in 3T3-L1 cells significantly increases Ucp1 expression in response to forskolin. Finally, double knockdown of both Zfp238 and Foxo1 normalizes Ucp1 induction. These data suggest that Zfp238 in adipose tissue regulates the thermogenic program in cooperation with Foxo1.
Highlights
Obesity is an important risk factor for cardiovascular and kidney diseases, diabetes, some cancers, and musculoskeletal disorders (NCD Risk Factor Collaboration (NCD-RisC), 2016)
To confirm the interaction between Foxo1 and Zfp238, we co-transfected HEK293 cells with cMyc-tagged wild-type Foxo1 (WTFoxo1) or constitutively nuclear Foxo1 (CNFoxo1) (Nakae et al, 2006) and FLAGtagged Zfp238 (Yokoyama et al, 2009) and performed reciprocal immunoprecipitation/immunoblotting experiments in the presence of serum using anti-cMyc and anti-FLAG antibodies. These experiments showed that Zfp238 interacted with CNFoxo1, but not with WTFoxo1 (Figures 1A and 1B)
To investigate the subcellular localization of WTFoxo1 and Zfp238, we performed immunofluorescence using HEK293 co-transfected with cMyc-tagged WTFoxo1 and FLAG-tagged Zfp238 in the presence of serum
Summary
Obesity is an important risk factor for cardiovascular and kidney diseases, diabetes, some cancers, and musculoskeletal disorders (NCD Risk Factor Collaboration (NCD-RisC), 2016). It is important to understand how obesity arises and how it can be prevented and treated. Adaptive thermogenesis is defined as heat production in response to cold exposure or overfeeding, protecting the organism from cold, or regulating energy balance after changes in diet. Brown adipose tissue (BAT) and skeletal muscle are the two major organs involved in adaptive thermogenesis (Cannon et al, 1998). Rodents have prominent brown fat depots, whereas larger mammals including humans do not, there may be brown adipocytes dispersed among white adipose tissue (WAT) (Rosen and Spiegelman, 2006)
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