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Publication
Wnt/ß-catenin signaling regulates adipose tissue lipogenesis and
adipocyte-specific loss is rigorously defended by neighboring stromal-vascular
cells.
Authors Bagchi DP, Nishii A, Li Z, DelProposto JB, Corsa CA, Mori H, Hardij J, Learman
BS, Lumeng CN, MacDougald OA
Submitted By Submitted Externally on 11/10/2020
Status Published
Journal Molecular metabolism
Year 2020
Date Published 9/1/2020
Volume : Pages 42 : 101078
PubMed Reference 32919095
Abstract Canonical Wnt/ß-catenin signaling is a well-studied endogenous regulator of
mesenchymal cell fate determination, promoting osteoblastogenesis and inhibiting
adipogenesis. However, emerging genetic evidence in humans links a number of Wnt
pathway members to body fat distribution, obesity, and metabolic dysfunction,
suggesting that this pathway also functions in adipocytes. Recent studies in
mice have uncovered compelling evidence that the Wnt signaling pathway plays
important roles in adipocyte metabolism, particularly under obesogenic
conditions. However, complexities in Wnt signaling and differences in
experimental models and approaches have thus far limited our understanding of
its specific roles in this context., To investigate roles of the canonical Wnt
pathway in the regulation of adipocyte metabolism, we generated
adipocyte-specific ß-catenin (ß-cat) knockout mouse and cultured cell models. We
used RNA sequencing, ChIP sequencing, and molecular approaches to assess
expression of Wnt targets and lipogenic genes. We then used functional assays to
evaluate effects of ß-catenin deficiency on adipocyte metabolism, including
lipid and carbohydrate handling. In mice maintained on normal chow and high-fat
diets, we assessed the cellular and functional consequences of
adipocyte-specific ß-catenin deletion on adipose tissues and systemic
metabolism., We report that in adipocytes, the canonical Wnt/ß-catenin pathway
regulates de novo lipogenesis (DNL) and fatty acid monounsaturation. Further,
ß-catenin mediates effects of Wnt signaling on lipid metabolism in part by
transcriptional regulation of Mlxipl and Srebf1. Intriguingly,
adipocyte-specific loss of ß-catenin is sensed and defended by CD45-/CD31-
stromal cells to maintain tissue-wide Wnt signaling homeostasis in chow-fed
mice. With long-term high-fat diet, this compensatory mechanism is overridden,
revealing that ß-catenin deletion promotes resistance to diet-induced obesity
and adipocyte hypertrophy and subsequent protection from metabolic dysfunction.,
Taken together, our studies demonstrate that Wnt signaling in adipocytes is
required for lipogenic gene expression, de novo lipogenesis, and lipid
desaturation. In addition, adipose tissues rigorously defend Wnt signaling
homeostasis under standard nutritional conditions, such that stromal-vascular
cells sense and compensate for adipocyte-specific loss. These findings
underscore the critical importance of this pathway in adipocyte lipid metabolism
and adipose tissue function.





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