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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
Published on: June 3, 2016
Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-gamma
Tetsuya Hosooka1, Tetsuya Noguchi, Ko Kotani
1Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Abstract:
Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin, but other substrates of the insulin receptor kinase, such as Gab1, c-Cbl, SH2-B and APS, are also of physiological relevance. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling, its role in energy homeostasis has remained unclear. Here we show that Dok1 regulates adiposity. Expression of Dok1 in white adipose tissue was markedly increased in mice fed a high-fat diet, whereas adipocytes lacking this adapter were smaller and showed a reduced hypertrophic response to this dietary manipulation. Dok1-deficient mice were leaner and showed improved glucose tolerance and insulin sensitivity compared with wild-type mice. Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR)-gamma on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR-gamma blocked development of the lean phenotype caused by Dok1 ablation. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-gamma and may thus confer predisposition to diet-induced obesity.
Insights
Protein downstream of tyrosine kinases-1 (Dok1) regulates fat storage and metabolism. Dok1 deficiency improves insulin sensitivity and glucose tolerance, offering insights into diet-induced obesity.
Area of Science:
- Metabolic signaling
- Obesity research
- Adipogenesis
Background:
- Insulin receptor substrates (IRS)-1 and IRS-2 are key in insulin action.
- Other insulin receptor kinase substrates like Gab1, c-Cbl, SH2-B, and APS are physiologically relevant.
- Protein downstream of tyrosine kinases-1 (Dok1) is a known multisite adapter in insulin signaling, but its role in energy homeostasis is unclear.
Purpose of the Study:
- To investigate the role of Dok1 in energy homeostasis and adiposity.
- To determine Dok1's function in diet-induced obesity and insulin sensitivity.
Main Methods:
- Examined Dok1 expression in white adipose tissue of mice on a high-fat diet.
- Analyzed adipocyte size and hypertrophic response in Dok1-deficient mice.
- Assessed glucose tolerance and insulin sensitivity in Dok1-deficient mice.
- Investigated adipogenic differentiation in Dok1-deficient embryonic fibroblasts.
- Measured ERK activity and PPAR-gamma phosphorylation at Ser112.
Main Results:
- Dok1 expression increased in white adipose tissue with high-fat diet.
- Dok1-deficient adipocytes were smaller with reduced hypertrophy.
- Dok1-deficient mice exhibited leanness, improved glucose tolerance, and insulin sensitivity.
- Dok1-deficient fibroblasts showed impaired adipogenic differentiation.
- This impairment correlated with increased ERK activity and PPAR-gamma phosphorylation at Ser112.
Conclusions:
- Dok1 promotes adipocyte hypertrophy and contributes to diet-induced obesity.
- Dok1 counteracts ERK's inhibitory effect on PPAR-gamma transactivation.
- Dok1 plays a significant role in regulating adiposity and energy homeostasis.
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