Depletion of white adipocyte progenitors induces beige adipocyte differentiation and suppresses obesity development

Daquinag, Alexes C.; Tseng, Chieh; Salameh, Ahmad; Zhang, Y.; Amaya-Manzanares, Felipe; Dadbin, Ali; Florez, Fernando Luis Esteban; Xu, Yuanzhong; Tong, Qingchun; Kolonin, Mikhail G.

doi:10.1038/cdd.2014.148

Cited by 55 publications

(89 citation statements)

References 62 publications

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“…Interestingly, beige fat displays a smooth muscle-like signature of gene expression profiles (190), suggesting a potential lineage relationship between beige adipocytes and smooth muscle cells. Diverse beige progenitor lineages may exist; in mice, both beige adipocyte-specific progenitors and beige/white adipocyte-bipotent PDGFRα + progenitors have been reported (60, 178, 338). Notably, a subpopulation of PDGFRα + mesenchymal progenitors (PDGFRα + CD9 high ) also differentiates into fibrogenic cells in obesity, promoting adipose tissue fibrosis (201).…”

Section: Bat and Beige Fat Developmentmentioning

confidence: 99%

Brown and Beige Adipose Tissues in Health and Disease

Rui

2017

Comprehensive Physiology

146

113

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Brown and beige adipocytes arise from distinct developmental origins. Brown adipose tissue (BAT) develops embryonically from precursors that also give to skeletal muscle. Beige fat develops postnatally and is highly inducible. Beige fat recruitment is mediated by multiple mechanisms, including de novo beige adipogenesis and white-to-brown adipocyte transdifferentiaiton. Beige precursors reside around vasculatures, and proliferate and differentiate into beige adipocytes. PDGFRα+Ebf2+ precursors are restricted to beige lineage cells, while another PDGFRα+ subset gives rise to beige adipocytes, white adipocytes, or fibrogenic cells. White adipocytes can be reprogramed and transdifferentiated into beige adipocytes. Brown and beige adipocytes display many similar properties, including multilocular lipid droplets, dense mitochondria, and expression of UCP1. UCP1-mediated thermogenesis is a hallmark of brown/beige adipocytes, albeit UCP1-independent thermogenesis also occurs. Development, maintenance, and activation of BAT/beige fat are guided by genetic and epigenetic programs. Numerous transcriptional factors and coactivators act coordinately to promote BAT/beige fat thermogenesis. Epigenetic reprograming also influences expression of brown/beige adipocyte-selective genes. BAT/beige fat is regulated by neuronal, hormonal, and immune mechanisms. Hypothalamic thermal circuits define the temperature setpoint that guides BAT/beige fat activity. Metabolic hormones, paracrine/autocrine factors, and various immune cells also play a critical role in regulating BAT/beige fat functions. BAT and beige fat defend temperature homeostasis, and regulate body weight and glucose and lipid metabolism. Obesity is associated with brown/beige fat deficiency, and reactivation of brown/beige fat provides metabolic health benefits in some patients. Pharmacological activation of BAT/beige fat may hold promise for combating metabolic diseases.

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Section: Bat and Beige Fat Developmentmentioning

confidence: 99%

Brown and Beige Adipose Tissues in Health and Disease

Rui

2017

Comprehensive Physiology

146

113

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“…Daquinag et al [40] have shown that targeted WAP cytoablation results in a long-term WAT growth suppression, despite increased caloric intake in a mouse model of dietary-induced obesity. They also showed that WAP depletion results in a compensatory population of beige adipocytes.…”

Section: Potential Effect Of Intervention Upon Wap Cells On Obesity Dmentioning

confidence: 99%

“…Consistent with the reported thermogenic capacity of the later tissue, WAP-depleted mice display increased energy expenditure. Thus, targeting white adipocyte progenitors could render an effective strategy to sustained modulation of WAT metabolic activity [40] .…”

Section: Potential Effect Of Intervention Upon Wap Cells On Obesity Dmentioning

confidence: 99%

White Adipose Tissue and Circadian Rhythm Dysfunctions in Obesity: Pathogenesis and Available Therapies

2016

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A combined neuroendocrine, metabolic, and chronobiological view can help to better understand the multiple and complex mechanisms involved in obesity development and maintenance, as well as to provide new effective approaches for its control and treatment. Indeed, we have currently updated data on the whole adipogenic process involved in white adipose tissue (WAT) mass expansion, namely due to a mechanism whereby WAT cells become hypertrophic, thus inducing a serious local (WAT) inflammatory condition that in turn, will impair not only the cross-talk between the hypothalamus and the WAT, but also favoring the development of deep and widespread neuroendocrine-metabolic dysfunction. Moreover, we also have revisited the circadian clock genes involved in dysfunctional WAT mass expansion and the mechanisms that may lead to obesity development, including early metabolic dysfunctions, enhanced oxidative stress and distorted energy homeostasis. The epigenetic changes of clock genes driving metabolic disease and obesity development have also been included in this review. Finally, we have also underlined the relevance of metabolic homeostasis regulation by central and peripheral organ clocks, sleep disturbances, nutrients, and feeding time, as key factors in obesity development as well as both, classical and chronotherapeutic approaches for its prevention and treatment.

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“…EO771 cells were then grafted into the mammary fat pad and tumors were allowed to form. Formalin-fixed paraffin-embedded tissues were sectioned and analyzed by immunofluorescence as described 49,50 using anti-IL-22 bs-2623R (Bioss, 1:100) and anti-IL-22R bs-2624R (Bioss, 1:200) antibodies, followed by secondary Alexa 488-conjugated and Cy3-conjugated antibodies. Nuclei were visualized with DAPI staining.…”

Section: Systemic Circulation Of Il-22 Is Increased In Obesitymentioning

confidence: 99%

“…Experimental compounds targeting adipose stroma prevented diet-induced obesity and tumor growth in mouse models. 44,49 Future studies will establish if this approach can complement approved anti-obesity and anti-cancer treatments. …”

Section: Infiltration Of Wat By Il-22-expressing Leukocytes and Il-22mentioning

confidence: 99%

Cytokine signaling regulating adipose stromal cell trafficking

Zhang

Kolonin

2016

Adipocyte

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Adipocyte progenitors, known as adipose stromal cells (ASC), can become mobilized, recruited by tumors, and contribute to cancer progression. Mechanisms underlying ASC trafficking have remained obscure. We recently reported that CXCL1 expressed by cancer cells chemoattracts ASC expressing CXCR1 in obesity. As a candidate mechanism of CXCL1 activation, we identified interleukin (IL)-22, systemic circulation of which is increased in obesity. It has been reported that IL-22 signaling through IL-22R is upstream of CXCL1. Here, we provide evidence that IL-22 expression by leukocytes infiltrating WAT and IL-22R expression by tumors is obesity-dependent. We propose that obesity-associated adipocyte death and the resulting recruitment of leukocytes triggers the IL-22 signaling cascade that induces CXCL1 secretion by cancer cells responsible for ASC trafficking to tumors. KEYWORDS adipose stromal cell; cytokine; chemokine; CXCL1; cancer; interleukin-22; receptor; obesity Epidemiology studies have indicated that progression of many cancers is associated with obesity. 1-5 Excess white adipose tissue (WAT) directly contributes to disease progression, alongside with obesity-associated lifestyle and diet. 6,7 Our studies using mouse models have shown that excess of WAT, which is overgrown in obese individuals, promotes tumor growth irrespective of diet used to induce obesity. 8,9 WAT is composed by adipocytes and vascular/stromal cells. 10,11 Adipose stromal cells (ASC) serve as the mesenchymal progenitors of adipocytes and as endothelium-supporting perivascular cells 12-14 with potent angiogenic capacity. 15 While malignant cells with ASC properties comprise an integral component of liposarcomas, tumors derived from WAT, 16 it is benign ASC that promote carcinoma progression. Along with other WAT cells, ASC secrete hormones, inflammatory cytokines, and growth factors collectively termed adipokines, many of which have pro-tumorigenic properties. 17,18 It has been discovered that, like bone marrow mesenchymal stem cells (MSC), 19 ASC can become mobilized and traffic outside WAT. [20][21][22] Because numbers of ASC increase in obesity, we had hypothesized that WAT is a contributor to the pool of tumor stromal cells. 23,24 We have identified ASC trafficking to tumors as the mechanism underlying the obesity-cancer link. In animal studies, administered ASC engraft tumors, which results in accelerated cancer progression. 8,9,[25][26][27] Our findings confirmed by data from other laboratories demonstrate tumor homing of endogenous ASC in obesity, which is concomitant with increased vascularization and adipogenesis promoting survival and proliferation of neighboring malignant cells. [28][29][30][31][32] The apparent contribution of ASC to the tumor stroma has raised a question regarding the safety of lipotransfer procedures in cancer patients. 33,34 Specific molecular mechanisms through which ASC promote cancer are being investigated, and it is becoming apparent that paracrine factors secreted by ASC within the tumor larg...

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Depletion of white adipocyte progenitors induces beige adipocyte differentiation and suppresses obesity development

Cited by 55 publications

References 62 publications

Brown and Beige Adipose Tissues in Health and Disease

Brown and Beige Adipose Tissues in Health and Disease

White Adipose Tissue and Circadian Rhythm Dysfunctions in Obesity: Pathogenesis and Available Therapies

Cytokine signaling regulating adipose stromal cell trafficking

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