Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone Fragility

Tencerová, Michaela; Frost, Morten; Figeac, Florence; Nielsen, Tina; Ali, Dalia; Lauterlein, Jens Jacob Lindegaard; Andersen, Thomas Levin; Haakonsson, Anders K; Rauch, Alexander; Madsen, Jonna Skov; Ejersted, Charlotte; Højlund, Kurt; Kassem, Moustapha

doi:10.1016/j.celrep.2019.04.066

Cited by 96 publications

(108 citation statements)

References 80 publications

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“…The authors clearly show that the local signaling of leptin in bone marrow stromal precursors, during obesity, is essential for the adipocyte commitment and differentiation (19). In another work, Tencerova et al (50) showed that LepR-positive BM-MSCs of obese individuals are more likely to differentiate into adipocytes, and that the silencing of LepR in BM-MSCs from obese individuals favored osteogenesis and reduced adipogenesis, with decreased expression of several adipogenesis-associated genes, alongside the impairment of the staining for lipid droplets (50). These results indicate that leptin's local effect may contribute in vivo to adipogenesis.…”

Section: Discussionmentioning

confidence: 93%

“…As stated above, the timing of leptin's treatment is of paramount importance for the outcomes observed in differentiated cells, with an early treatment of precursor cells leading to a proadipogenic leptin signaling. Sustaining this hypothesis, the specific knockout of LepR in already mature adipocytes did not have important effects on adipogenesis (49), while the specific knockout or knockdown of LepR in precursor cells impaired their ability to commit to the adipocyte fate (19,50). Yue et al (19) showed that the specific deletion of the leptin receptor LepR gene in the bone marrow-derived mesenchymal stromal cells (BM-MSCs) favored osteogenesis at the expense of adipogenesis within the bone marrow (19).…”

Section: Discussionmentioning

confidence: 99%

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Leptin Induces Proadipogenic and Proinflammatory Signaling in Adipocytes

et al. 2019

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Background: Leptin is an adipokine with well-known effects on the central nervous system including the induction of energy expenditure and satiety. Leptin also has major relevance when activating immune cells and modulating inflammatory response. In obesity, increases in white adipose tissue accumulation and leptin levels are accompanied by hypothalamic resistance to leptin. Even though the adipose tissue is a leptin-rich environment, the local actions of leptin regarding adipogenesis were not thoroughly investigated until now. Here we evaluate the contributions of leptins direct signaling in preadipocytes and adipose tissue-derived stromal cells (ASCs) for adipogenesis.Methods: Adipocytes were differentiated from the murine lineage of preadipocytes 3T3-L1 or ASCs from subcutaneous and visceral (retroperitoneal) fat depots from C57Bl/6J mice. Differentiating cells were treated with leptin in addition to or in replacement of insulin. The advance of adipogenesis was assessed by the expression and secretion of adipogenesis-and lipogenesis-related proteins by Western blot and immunoenzimatic assays, and the accumulation of lipid droplets by fluorescence microscopy.Results: Leptin treatment in 3T3-L1 preadipocytes or ASCs increased the production of the adipogenesis-and lipogenesis-related proteins PLIN1, CAV-1, PPARγ, SREBP1C, and/or adiponectin at earlier stages of differentiation. In 3T3-L1 preadipocytes, we found that leptin induced lipid droplets' formation in an mTOR-dependent manner. Also, leptin induced a proinflammatory cytokine profile in 3T3-L1 and ASCs, modulating the production of TNF-α, IL-10, and IL-6. Since insulin is considered an essential factor for preadipocyte differentiation, we asked whether leptin would support adipogenesis in the absence of insulin. Importantly, leptin induced the formation of lipid droplets and the expression of adipogenesis-related proteins independently of insulin during the differentiation of 3T3-L1 cells and ASCs. Conclusions:Our results demonstrate that leptin induces intracellular signaling in preadipocytes and adipocytes promoting adipogenesis and modulating the secretion Palhinha et al.Leptin Induces Adipogenesis of inflammatory mediators. Also, leptin restores adipogenesis in the absence of insulin. These findings contribute to the understanding of the local signaling of leptin in precursor and mature adipose cells. The proadipogenic role of leptin unraveled here may be of especial relevance during obesity, when its central signaling is defective.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Leptin Induces Proadipogenic and Proinflammatory Signaling in Adipocytes

et al. 2019

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“…Our findings also have implications for BMAT lipid metabolism. Adipocyte-specific ablation of Insr in mice decreases BMAd size 4 , suggesting a role for insulin in BMAd lipogenesis; however, it is unclear if this is through de novo lipogenesis from glucose, via insulin regulating uptake and esterification of fatty acids, or through stimulation by insulin of BMSC adipogenesis 38 . We show that BMAT is capable of insulin-stimulated Akt S473 phosphorylation, a modification implicated in lipogenesis downstream of mTORC2 activation 39 ; however, it is unclear how this might stimulate lipogenesis in the absence of Akt T308 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis

et al. 2020

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Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass, yet unlike white or brown adipose tissues (WAT or BAT) its metabolic functions remain unclear. Herein, we address this critical gap in knowledge. Our transcriptomic analyses revealed that BMAT is distinct from WAT and BAT, with altered glucose metabolism and decreased insulin responsiveness. We therefore tested these functions in mice and humans using positron emission tomography-computed tomography (PET/CT) with 18 F-fluorodeoxyglucose. This revealed that BMAT resists insulin-and cold-stimulated glucose uptake, while further in vivo studies showed that, compared to WAT, BMAT resists insulin-stimulated Akt phosphorylation. Thus, BMAT is functionally distinct from WAT and BAT. However, in humans basal glucose uptake in BMAT is greater than in axial bones or subcutaneous WAT and can be greater than that in skeletal muscle, underscoring the potential of BMAT to influence systemic glucose homeostasis. These PET/CT studies characterise BMAT function in vivo, establish new methods for BMAT analysis, and identify BMAT as a distinct, major adipose tissue subtype.

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“…33 Another recent study found that, in human bone marrow stromal cells, greater ROS concentrations in obesity enhanced insulin signalling by increasing the abundance of insulin and leptin receptors. 34 The subsequent increase in oxidative phosphorylation of glucose lead to a redox imbalance with ensuing stem cell exhaustion and accelerated bone marrow micro-environment senescence conducive to bone fragility, which is commonly observed in the aged population. Furthermore, excessive ROS in obesity promotes changes in human adipose tissue that are characteristic of ageing.…”

Section: Obesity Induces a Redox Imbalance Similar To Ageingmentioning

confidence: 99%

Obesity and ageing: Two sides of the same coin

2020

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Summary Conditions and comorbidities of obesity mirror those of ageing and age‐related diseases. Obesity and ageing share a similar spectrum of phenotypes such as compromised genomic integrity, impaired mitochondrial function, accumulation of intracellular macromolecules, weakened immunity, shifts in tissue and body composition, and enhanced systemic inflammation. Moreover, it has been shown that obesity reduces life expectancy by 5.8 years in men and 7.1 years in women after the age of 40. Shorter life expectancy could be because obesity holistically accelerates ageing at multiple levels. Besides jeopardizing nuclear DNA and mitochondrial DNA integrity, obesity modifies the DNA methylation pattern, which is associated with epigenetic ageing in different tissues. Additionally, other signs of ageing are seen in individuals with obesity including telomere shortening, systemic inflammation, and functional declines. This review aims to show how obesity and ageing are “two sides of the same coin” through discussing how obesity predisposes an individual to age‐related conditions, illness, and disease. We will further demonstrate how the mechanisms that perpetuate the early‐onset of chronic diseases in obesity parallel those of ageing.

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Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone Fragility

Cited by 96 publications

References 80 publications

Leptin Induces Proadipogenic and Proinflammatory Signaling in Adipocytes

Leptin Induces Proadipogenic and Proinflammatory Signaling in Adipocytes

Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis

Obesity and ageing: Two sides of the same coin

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