Engineering fat cell fate to fight obesity and metabolic diseases

Abstract Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.

Download Full-text

Scd1 controls de novo beige fat biogenesis through succinate-dependent regulation of mitochondrial complex II

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1914553117 ◽

2020 ◽

Vol 117 (5) ◽

pp. 2462-2472 ◽

Cited By ~ 6

Author(s):

Keli Liu ◽

Liangyu Lin ◽

Qing Li ◽

Yueqing Xue ◽

Fanjun Zheng ◽

...

Keyword(s):

Cell Fate ◽

Metabolic Diseases ◽

De Novo ◽

Great Promise ◽

Mitochondrial Complex ◽

Differentiation Potential ◽

Complex Ii ◽

White Adipocytes ◽

Beige Adipocytes ◽

Adipocyte Progenitors

Preadipocytes can give rise to either white adipocytes or beige adipocytes. Owing to their distinct abilities in nutrient storage and energy expenditure, strategies that specifically promote “beiging” of adipocytes hold great promise for counterbalancing obesity and metabolic diseases. Yet, factors dictating the differentiation fate of adipocyte progenitors remain to be elucidated. We found that stearoyl-coenzyme A desaturase 1 (Scd1)-deficient mice, which resist metabolic stress, possess augmentation in beige adipocytes under basal conditions. Deletion of Scd1 in mature adipocytes expressing Fabp4 or Ucp1 did not affect thermogenesis in mice. Rather, Scd1 deficiency shifted the differentiation fate of preadipocytes from white adipogenesis to beige adipogenesis. Such effects are dependent on succinate accumulation in adipocyte progenitors, which fuels mitochondrial complex II activity. Suppression of mitochondrial complex II by Atpenin A5 or oxaloacetic acid reverted the differentiation potential of Scd1-deficient preadipocytes to white adipocytes. Furthermore, supplementation of succinate was found to increase beige adipocyte differentiation both in vitro and in vivo. Our data reveal an unappreciated role of Scd1 in determining the cell fate of adipocyte progenitors through succinate-dependent regulation of mitochondrial complex II.

Download Full-text

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

Scientific Reports ◽

10.1038/s41598-019-56237-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Theres Schaub ◽

Dennis Gürgen ◽

Deborah Maus ◽

Claudia Lange ◽

Victor Tarabykin ◽

...

Keyword(s):

Cell Fate ◽

Mesenchymal Stromal Cells ◽

Cellular Senescence ◽

Stromal Cells ◽

Metabolic Diseases ◽

Osteoblastic Differentiation ◽

Cell Fates ◽

Network Activation ◽

Vascular Regeneration ◽

Age Related

AbstractVascular regeneration depends on intact function of progenitors of vascular smooth muscle cells such as pericytes and their circulating counterparts, mesenchymal stromal cells (MSC). Deregulated MSC differentiation and maladaptive cell fate programs associated with age and metabolic diseases may exacerbate arteriosclerosis due to excessive transformation to osteoblast-like calcifying cells. Targeting mTOR, a central controller of differentiation and cell fates, could offer novel therapeutic perspectives. In a cell culture model for osteoblastic differentiation of pluripotent human MSC we found distinct roles for mTORC1 and mTORC2 in the regulation of differentiation towards calcifying osteoblasts via cell fate programs in a temporally-controlled sequence. Activation of mTORC1 with induction of cellular senescence and apoptosis were hallmarks of transition to a calcifying phenotype. Inhibition of mTORC1 with Rapamycin elicited reciprocal activation of mTORC2, enhanced autophagy and recruited anti-apoptotic signals, conferring protection from calcification. Pharmacologic and genetic negative interference with mTORC2 function or autophagy both abolished regenerative programs but induced cellular senescence, apoptosis, and calcification. Overexpression of the mTORC2 constituent rictor revealed that enhanced mTORC2 signaling without altered mTORC1 function was sufficient to inhibit calcification. Studies in mice reproduced the in vitro effects of mTOR modulation with Rapamycin on cell fates in vascular cells in vivo. Amplification of mTORC2 signaling promotes protective cell fates including autophagy to counteract osteoblast differentiation and calcification of MSC, representing a novel mTORC2 function. Regenerative approaches aimed at modulating mTOR network activation patterns hold promise for delaying age-related vascular diseases and treatment of accelerated arteriosclerosis in chronic metabolic conditions.

Download Full-text

Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1010929108 ◽

2010 ◽

Vol 108 (1) ◽

pp. 143-148 ◽

Cited By ~ 314

Author(s):

Tim J. Schulz ◽

Tian Lian Huang ◽

Thien T. Tran ◽

Hongbin Zhang ◽

Kristy L. Townsend ◽

...

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Cell Fate ◽

Brown Fat ◽

Brown Adipocyte ◽

Molecular Characteristics ◽

Fat Cell ◽

Interscapular Brown Adipose Tissue ◽

Brown Adipose ◽

White Fat

Brown fat is specialized for energy expenditure and has therefore been proposed to function as a defense against obesity. Despite recent advances in delineating the transcriptional regulation of brown adipocyte differentiation, cellular lineage specification and developmental cues specifying brown-fat cell fate remain poorly understood. In this study, we identify and isolate a subpopulation of adipogenic progenitors (Sca-1+/CD45−/Mac1−; referred to as Sca-1+ progenitor cells, ScaPCs) residing in murine brown fat, white fat, and skeletal muscle. ScaPCs derived from different tissues possess unique molecular expression signatures and adipogenic capacities. Importantly, although the ScaPCs from interscapular brown adipose tissue (BAT) are constitutively committed brown-fat progenitors, Sca-1+ cells from skeletal muscle and subcutaneous white fat are highly inducible to differentiate into brown-like adipocytes upon stimulation with bone morphogenetic protein 7 (BMP7). Consistent with these findings, human preadipocytes isolated from subcutaneous white fat also exhibit the greatest inducible capacity to become brown adipocytes compared with cells isolated from mesenteric or omental white fat. When muscle-resident ScaPCs are re-engrafted into skeletal muscle of syngeneic mice, BMP7-treated ScaPCs efficiently develop into adipose tissue with brown fat-specific characteristics. Importantly, ScaPCs from obesity-resistant mice exhibit markedly higher thermogenic capacity compared with cells isolated from obesity-prone mice. These data establish the molecular characteristics of tissue-resident adipose progenitors and demonstrate a dynamic interplay between these progenitors and inductive signals that act in concert to specify brown adipocyte development.

Download Full-text

Determining Fat Cell Fate

Science Signaling ◽

10.1126/stke.2000.53.tw12 ◽

2000 ◽

Vol 2000 (53) ◽

pp. tw12-tw12

Keyword(s):

Cell Fate ◽

Fat Cell

Download Full-text

Sphingolipids and Mitochondrial Dynamic

Cells ◽

10.3390/cells9030581 ◽

2020 ◽

Vol 9 (3) ◽

pp. 581 ◽

Cited By ~ 6

Author(s):

Lais Brigliadori Fugio ◽

Fernanda B. Coeli-Lacchini ◽

Andréia Machado Leopoldino

Keyword(s):

Cell Fate ◽

Metabolic Diseases ◽

Mitochondrial Dynamics ◽

Mitochondrial Dynamic ◽

Sphingosine 1 Phosphate ◽

Mitochondria Dynamics ◽

Human Disorders ◽

Cell Type Specific ◽

Immune System Regulation ◽

Ceramide Synthases

For decades, sphingolipids have been related to several biological functions such as immune system regulation, cell survival, and proliferation. Recently, it has been reported that sphingolipids could be biomarkers in cancer and in other human disorders such as metabolic diseases. This is evidenced by the biological complexity of the sphingolipids associated with cell type-specific signaling and diverse sphingolipids molecules. As mitochondria dynamics have serious implications in homeostasis, in the present review, we focused on the relationship between sphingolipids, mainly ceramides and sphingosine-1-phosphate, and mitochondrial dynamics directed by fission, fusion, and mitophagy. There is evidence that the balances of ceramides (C18 and C16) and S1P, as well as the location of specific ceramide synthases in mitochondria, have roles in mitophagy and fission with an impact on cell fate and metabolism. However, signaling pathways controlling the sphingolipids metabolism and their location in mitochondria need to be better understood in order to propose new interventions and therapeutic strategies.

Download Full-text

Metabolic signaling functions of ER–mitochondria contact sites: role in metabolic diseases

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0189 ◽

2017 ◽

Vol 58 (2) ◽

pp. R87-R106 ◽

Cited By ~ 44

Author(s):

Emily Tubbs ◽

Jennifer Rieusset

Keyword(s):

Cell Fate ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Treatment Strategies ◽

Contact Sites ◽

Novel Treatment ◽

Functional Features ◽

Novel Treatment Strategies

Beyond the maintenance of cellular homeostasis and the determination of cell fate, ER–mitochondria contact sites, defined as mitochondria-associated membranes (MAM), start to emerge as an important signaling hub that integrates nutrient and hormonal stimuli and adapts cellular metabolism. Here, we summarize the established structural and functional features of MAM and mainly focus on the latest breakthroughs highlighting a crucial role of organelle crosstalk in the control of metabolic homeostasis. Lastly, we discuss recent studies that have revealed the importance of MAM in not only metabolic diseases but also in other pathologies with disrupted metabolism, shedding light on potential common molecular mechanisms and leading hopefully to novel treatment strategies.

Download Full-text

serpent, a GATA-like transcription factor gene, induces fat-cell development in Drosophila melanogaster

Development ◽

10.1242/dev.128.7.1193 ◽

2001 ◽

Vol 128 (7) ◽

pp. 1193-1200

Author(s):

S.A. Hayes ◽

J.M. Miller ◽

D.K. Hoshizaki

Keyword(s):

Transcription Factor ◽

Cell Fate ◽

Body Wall ◽

Body Wall Muscle ◽

Ectopic Fat ◽

Fat Cells ◽

Transcription Factor Gene ◽

Fat Cell ◽

Factor Gene ◽

Visceral Mesoderm

The GATA-like transcription factor gene serpent is necessary for embryonic fat-cell differentiation in Drosophila (Sam, S., Leise, W. and Hoshizaki, D. K. (1996) Mech. Dev. 60, 197–205) and has been proposed to function in a cell-fate choice between fat cell and somatic gonadal precursors (Moore, L. A., Broihier, H. T., Van Doren, M. and Lehmann, R. (1998) Development 125, 837–44; Riechmann, V., Irion, U., Wilson, R., Grosskortenhaus, R. and Leptin, M. (1997) Development 124, 2915–22). Here, we report that deregulated expression of serpent in the mesoderm induces the formation of ectopic fat cells and prevents the migration and coalescence of the somatic gonadal precursors. The ectopic fat cells do not arise from hyperproliferation of the primary fat-cell clusters but they do associate with the endogenous fat cells to form a fat body that is expanded in both the dorsal/ventral and anterior/posterior axes. Misexpression of serpent also affects the differentiation of muscle cells. Few body-wall muscle precursors are specified and there is a loss of most body-wall muscle fibers. The precursors of the visceral mesoderm are also absent and concomitantly the visceral muscle is absent. We suggest that the ectopic fat cells might originate from cells that have the potential, but do not normally, differentiate into fat cells or from cells that have acquired a fat-cell fate. In light of our results, we discuss the role of serpent in fat-cell specification and in cell fate choices.

Download Full-text