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Akt3 inhibits adipogenesis and protects from diet-induced obesity via WNK1/SGK1 signaling
Liang Ding, … , Tatiana Byzova, Eugene Podrez
Liang Ding, … , Tatiana Byzova, Eugene Podrez
Published November 16, 2017
Citation Information: JCI Insight. 2017;2(22):e95687. https://doi.org/10.1172/jci.insight.95687.
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Research Article Metabolism

Akt3 inhibits adipogenesis and protects from diet-induced obesity via WNK1/SGK1 signaling

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Abstract

Three Akt isoforms, encoded by 3 separate genes, are expressed in mammals. While the roles of Akt1 and Akt2 in metabolism are well established, it is not yet known whether Akt3 plays a role in metabolic diseases. We now report that Akt3 protects mice from high-fat diet–induced obesity by suppressing an alternative pathway of adipogenesis via with no lysine protein kinase-1 (WNK1) and serum/glucocorticoid-inducible kinase 1 (SGK1). We demonstrate that Akt3 specifically phosphorylates WNK1 at T58 and promotes its degradation via the ubiquitin-proteasome pathway. A lack of Akt3 in adipocytes increases the WNK1 protein level, leading to activation of SGK1. SGK1, in turn, promotes adipogenesis by phosphorylating and inhibiting transcription factor FOXO1 and, subsequently, activating the transcription of PPARγ in adipocytes. Akt3-deficient mice have an increased number of adipocytes and, when fed a high-fat diet, display increased weight gain, white adipose tissue expansion, and impaired glucose homeostasis. Pharmacological blockade of SGK1 in high-fat diet–fed Akt3-deficient mice suppressed adipogenesis, prevented excessive weight gain and adiposity, and ameliorated metabolic parameters. Thus, Akt3/WNK1/SGK1 represents a potentially novel signaling pathway controlling the development of obesity.

Authors

Liang Ding, Lifang Zhang, Sudipta Biswas, Rebecca C. Schugar, J. Mark Brown, Tatiana Byzova, Eugene Podrez

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Figure 1

Lack of Akt3 activity promotes preadipocyte differentiation into adipocytes.

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Lack of Akt3 activity promotes preadipocyte differentiation into adipocy...
(A) Microscopic images of WT, Akt1–/–, Akt2–/–, and Akt3–/– MEF at day 8 after induction of adipogenesis. Scale bars: 500 μm. n = 5. (B) Oil red O staining of Akt3–/– MEF–differentiated adipocytes after treatment with plasmid encoding Akt3 gene. Scale bar: 200 μm. n = 3. (C) Oil red O staining of 3T3 differentiated adipocytes after treatment with Akt1-specific siRNA, Akt3-specific siRNA, WT Akt3 plasmid, or mutant Akt3 (Akt3nmf350) plasmid. 3T3-L1 cells were transfected with indicated siRNA or plasmids for 24 hours before addition of differentiation medium. Scale bar: 50 μm. n = 5. (D) BODIPY 493/503 staining of 3T3 differentiated adipocytes after treatment with Akt1-specific siRNA, Akt3-specific siRNA, WT Akt3 plasmid, or mutant Akt3 (Akt3nmf350) plasmid. Scale bar: 100 μm. n = 5. (E) Adipogenesis in human s.c. preadipocytes treated with Akt3 siRNA. Scale bar: 200 μm. n = 3. (F) Western blot analysis of FABP4, C/EBPα, PPARγ, FAS, HSL, ATGL, MGL, and phosphorylation of HSL (Ser563) in WT and Akt3–/– MEF–differentiated adipocytes. Right graphs show densitometric quantification. n = 4. (G) The content of triglyceride in WT and Akt3–/– MEF before (control) or after (Diff) 1-week incubation in adipogenic media containing dexamethasone, insulin, and IBMX. n = 5. Data represent means ± SEM. *P < 0.05 by 2-tailed Student’s t test.

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