Wntless regulates lipogenic gene expression in adipocytes and protects against diet-induced metabolic dysfunction

Bagchi, Devika P.; Li, Ziru; Corsa, Callie A.S.; Hardij, Julie; Mori, Hiroyuki; Learman, Brian S.; Lewis, Kenneth T.; Schill, Rebecca L.; Romanelli, Steven M.; MacDougald, Ormond A.

doi:10.1016/j.molmet.2020.100992

Cited by 22 publications

(30 citation statements)

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“…The canonical Wnt/β-catenin pathway is a critical regulator of mesenchymal cell fate determination and an endogenous inhibitor of adipogenesis [ 15 , 16 ]. Although Wnt signaling is commonly believed to be most important in precursors, recent studies have begun to shed light on contributions of this pathway to functions within terminally-differentiated adipocytes [ [37] , [38] , [39] , [40] ]; however, specific roles of β-catenin in this context require further investigation. We thus first confirmed that β-catenin is expressed in mature adipocytes.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have demonstrated that Wnt signaling plays a role in adipocyte metabolism under obesogenic conditions [ [37] , [38] , [39] , [40] ]. Thus, we examined the regulation of β-catenin in WAT after a number of nutritional and environmental treatments and found that its expression is upregulated in both eWAT and iWAT with diet-induced obesity ( Figure 1 D), parallel with induction of Lep (leptin) ( Supplemental Figure 1C ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, β-cat −/− adipocytes also contained slightly elevated proportions of oleic (C18:1, n-9), vaccenic (C18:1, n-7), and arachidonic (C20:4) acids ( Supplemental Figure 3B , data not shown), consistent with previously published studies of SCD1 inhibition in 3T3-L1 adipocytes [ 65 ]. Although it is surprising that Elovl6 did not follow the expression pattern of other ChREBP- and SREBP1-regulated lipogenic genes, increased Elovl7 has been observed in various contexts of repressed Wnt signaling [ 40 , [66] , [67] , [68] ]. The functional significance of elevated ELOVL7 mRNA and protein remains unclear because we did not observe increased proportions of very long chain saturated fatty acids in β-cat −/− adipocytes (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Lipids were extracted from cultured adipocytes as previously described [ 40 ]. Briefly, cells were washed twice with PBS and then collected in 500 μl of a 1:2.5 methanol/water mixture.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, adipocyte-specific Tcf7l2 deletion in obese mice results in increased adipocyte hypertrophy and impaired glucose homeostasis [ 39 ]. Our lab has demonstrated that loss of Wntless, and thus signaling by adipocyte-derived Wnts, protects mice from diet-induced obesity and metabolic dysfunction [ 40 ]. Consistent with these findings, Chen et al.…”

Section: Introductionmentioning

confidence: 99%

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Wnt/β-catenin signaling regulates adipose tissue lipogenesis and adipocyte-specific loss is rigorously defended by neighboring stromal-vascular cells

Bagchi

Nishii

et al. 2020

Molecular Metabolism

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Objective Canonical Wnt/β-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. Methods To investigate roles of the canonical Wnt pathway in the regulation of adipocyte metabolism, we generated adipocyte-specific β-catenin ( β-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 β-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 β-catenin deletion on adipose tissues and systemic metabolism. Results We report that in adipocytes, the canonical Wnt/β-catenin pathway regulates de novo lipogenesis (DNL) and fatty acid monounsaturation. Further, β-catenin mediates effects of Wnt signaling on lipid metabolism in part by transcriptional regulation of Mlxipl and Srebf1 . Intriguingly, adipocyte-specific loss of β-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 β-catenin deletion promotes resistance to diet-induced obesity and adipocyte hypertrophy and subsequent protection from metabolic dysfunction. Conclusions 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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Lipids were extracted from cultured adipocytes as previously described [ 40 ]. Briefly, cells were washed twice with PBS and then collected in 500 μl of a 1:2.5 methanol/water mixture.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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