SnapShot: Niche Determines Adipocyte Character I

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.

Section: Methodsmentioning

confidence: 99%

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

Nishii

et al. 2020

Molecular Metabolism

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“…Adipocytes are found in white (WAT) and brown adipose tissues, as well as in bone marrow adipose tissue (BMAT) and other more minor depots 1–4 . Although adipocytes were identified in human bone marrow more than a century ago, the origin, development, function and interaction of these adipocytes with other cells within bone marrow were largely unstudied until recently 3, 5 .…”

Section: Introductionmentioning

confidence: 99%

Development, regulation, metabolism and function of bone marrow adipose tissues

Hardij

et al. 2018

Bone

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121

128

Most adipocytes exist in discrete depots throughout the body, notably in well-defined white and brown adipose tissues. However, adipocytes also reside within specialized niches, of which the most abundant is within bone marrow. Whereas bone marrow adipose tissue (BMAT) shares many properties in common with white adipose tissue, the distinct functions of BMAT are reflected by its development, regulation, protein secretion, and lipid composition. In addition to its potential role as a local energy reservoir, BMAT also secretes proteins, including adiponectin, RANK ligand, dipeptidyl peptidase-4, and stem cell factor, which contribute to local marrow niche functions and which may also influence global metabolism. The characteristics of BMAT are also distinct depending on whether marrow adipocytes are contained within yellow or red marrow, as these can be thought of as 'constitutive' and 'regulated', respectively. The rBMAT for instance can be expanded or depleted by myriad factors, including age, nutrition, endocrine status and pharmaceuticals. Herein we review the site specificity, age-related development, regulation and metabolic characteristics of BMAT under various metabolic conditions, including the functional interactions with bone and hematopoietic cells.

“…Adipose tissues play critical roles in whole-body homeostasis, including storage and release of energy in response to local and global needs, thermoregulation, and secretion of adipokines to regulate energy balance, metabolism and immune responses 1,2 . Adipocytes are distributed throughout the body in discrete depots, and in some cases serve specialized roles within their microenvironments 3,4,5 . Historically, the study of adipose tissue has centered on white adipose tissue (WAT), and its role in maintaining energy homeostasis.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to their location in major WAT and BAT depots, adipocytes exist in discrete niches throughout the body 4 , where they may perform specialized functions within their respective microenvironments. For example, bone marrow adipose tissue (BMAT) serves as a lipid reservoir, is a major source of circulating adiponectin, and closely interacts with osteoblasts, osteoclasts, and hematopoietic cells 10,11 .…”

Section: Introductionmentioning

confidence: 99%

Identification and Dissection of Diverse Mouse Adipose Depots

MacDougald

2019

JoVE

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Adipose tissues are complex organs with a wide array of functions, including storage and mobilization of energy in response to local and global needs, uncoupling of metabolism to generate heat, and secretion of adipokines to regulate whole-body homeostasis and immune responses. Emerging research is identifying important regional differences in the developmental, molecular, and functional profiles of adipocytes located in discrete depots throughout the body. Different properties of the depots are medically relevant since metabolic diseases often demonstrate depot-specific effects. This protocol will provide investigators with a detailed anatomic atlas and dissection guide for the reproducible and accurate identification and excision of diverse mouse adipose tissues. Standardized dissection of discrete adipose depots will allow detailed comparisons of their molecular and metabolic characteristics and contributions to local and systemic pathologic states under various nutritional and environmental conditions.