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Wntless regulates lipogenic gene expression in adipocytes and protects against
diet-induced metabolic dysfunction.
Bagchi DP, Li Z, Corsa CA, Hardij J, Mori H, Learman BS, Lewis KT, Schill RL,
Romanelli SM, MacDougald OA
Submitted Externally on 11/10/2020
Volume : Pages
39 : 100992
Obesity is a key risk factor for many secondary chronic illnesses, including
type 2 diabetes and cardiovascular disease. Canonical Wnt/ß-catenin signaling is
established as an important endogenous inhibitor of adipogenesis. This pathway
is operative in mature adipocytes; however, its roles in this context remain
unclear due to complexities of Wnt signaling and differences in experimental
models. In this study, we used novel cultured cell and mouse models to
investigate functional roles of Wnts secreted from adipocytes., We generated
adipocyte-specific Wntless (Wls) knockout mice and cultured cell models to
investigate molecular and metabolic consequences of disrupting Wnt secretion
from mature adipocytes. To characterize Wls-deficient cultured adipocytes, we
evaluated the expression of Wnt target and lipogenic genes and the downstream
functional effects on carbohydrate and lipid metabolism. We also investigated
the impact of adipocyte-specific Wls deletion on adipose tissues and global
glucose metabolism in mice fed normal chow or high-fat diets., Many aspects of
the Wnt signaling apparatus are expressed and operative in mature adipocytes,
including the Wnt chaperone Wntless. Deletion of Wntless in cultured adipocytes
results in the inhibition of de novo lipogenesis and lipid monounsaturation,
likely through repression of Srebf1 (SREBP1c) and Mlxipl (ChREBP) and impaired
cleavage of immature SREBP1c into its active form. Adipocyte-specific Wls
knockout mice (Wls-/-) have lipogenic gene expression in adipose tissues and
isolated adipocytes similar to that of controls when fed a normal chow diet.
However, closer investigation reveals that a subset of Wnts and downstream
signaling targets are upregulated within stromal-vascular cells of Wls-/- mice,
suggesting that adipose tissues defend loss of Wnt secretion from adipocytes.
Interestingly, this compensation is lost with long-term high-fat diet
challenges. Thus, after six months of a high-fat diet, Wls-/- mice are
characterized by decreased adipocyte lipogenic gene expression, reduced visceral
adiposity, and improved glucose homeostasis., Taken together, these studies
demonstrate that adipocyte-derived Wnts regulate de novo lipogenesis and lipid
desaturation and coordinate the expression of lipogenic genes in adipose
tissues. In addition, we report that Wnt signaling within adipose tissues is
defended, such that a loss of Wnt secretion from adipocytes is sensed and
compensated for by neighboring stromal-vascular cells. With chronic
overnutrition, this compensatory mechanism is lost, revealing that Wls-/- mice
are resistant to diet-induced obesity, adipocyte hypertrophy, and metabolic
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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