The Complex Roles of Mechanistic Target of Rapamycin in Adipocytes and Beyond

Lee, Peter L.; Jung, Sung-Min; Guertin, David A.

doi:10.1016/j.tem.2017.01.004

Cited by 53 publications

(51 citation statements)

References 194 publications

(240 reference statements)

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“…Accordingly, we observed significant downregulation of miR-496 with increasing obesity stages, suggesting a role of miR-496 also in the BMI-dependent regulation of mTOR. These findings are in line with our understanding that T2DM and obesity are strongly linked to the mTORC1 signaling pathway and dysfunctional adipose tissue [17][18][19]. Hence, mTOR is reported to regulate adipogenesis, which is vital for animals to maintain energy balance by storing lipids.…”

Section: Discussionsupporting

confidence: 86%

MicroRNA-496 and Mechanistic Target of Rapamycin Expression are Associated with Type 2 Diabetes Mellitus and Obesity in Elderly People

et al. 2019

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Background: Mechanistic target of rapamycin (mTOR) regulates lipid and glucose metabolism thus playing a key role in metabolic diseases like type 2 diabetes mellitus (T2DM). Recently, we demonstrated a functional interaction of microRNA-496 (miR-496) with mTOR and its impact on the regulation of human ageing. Objectives: As T2DM is most prevalent in older adults, we hypothesized that miR-496 may also have an impact on mTOR regulation in T2DM. Methods: Based on real-time PCR and enzyme-linked immunosorbent assay, mTOR gene and protein expression as well as miR-496 expression were monitored in peripheral blood mononuclear cells (PBMC) from T2DM patients (median age: 71) and healthy age- and BMI matched controls (median age: 69). Results: We demonstrated significant upregulation of phospho-mTOR and P70S6 Kinase (P70S6K) levels and significant downregulation of miR-496 in PBMC from elderly T2DM patients in comparison to a BMI and age-matched control cohort. Moreover, significant upregulation of phospho-mTOR protein and significant downregulation of miR-496 were observed in advanced stages of obesity. Conclusions: BMI-dependent upregulation of mTOR and the inverse expression profile of miR-496 observed in elderly T2DM patients suggest a correlation with T2DM. Hence, our results indicate a potential association of miR-496 with mTOR expression in elderly T2DM patients and obesity. Since phosphorylation of P70S6K was also elevated in T2DM patients, we conclude that mTOR signaling through TORC1 may be affected in the regulation of T2DM.

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Section: Discussionsupporting

confidence: 86%

MicroRNA-496 and Mechanistic Target of Rapamycin Expression are Associated with Type 2 Diabetes Mellitus and Obesity in Elderly People

et al. 2019

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“…The mammalian target of rapamycin (mTOR) kinase is a master regulator of intracellular metabolism that responds to insulin signaling and nutrient availability. Its biochemical functions are split between two complexes called mTOR complex 1 (mTORC1), which contains the essential subunit Raptor, and mTOR complex 2 (mTORC2), which contains the essential subunits Rictor and Sin1 1,2 . Amino acids and insulin stimulate mTORC1 to promote protein, lipid, and nucleic acid synthesis through well-defined downstream signaling networks.…”

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confidence: 99%

“…Many models show mTORC2 as an obligatory AKT activator 1,5 ; however, its exact function in downstream AKT signaling in vivo remains elusive because, in many tissue-specific conditional Rictor knockout (KO) models, mTORC2 loss has seemingly minimal-to-no effect on the phosphorylation of several AKT substrates 2,10 . For example, conditionally deleting Rictor in brown adipose tissue (BAT) (e.g., with ucp1-cre or myf5-cre) or in white adipose tissue (WAT) (with adiponectin-cre) ablates AKT HM phosphorylation without obviously impairing AKT activity toward classic substrates, including PRAS40, TSC2, GSK3β, AS160, and FoxO1 [10][11][12][13][14] .…”

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confidence: 99%

mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis

et al. 2020

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mTORC2 phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In brown adipocytes, mTORC2 regulates glucose and lipid metabolism, however the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate in brown preadipocytes. mTORC2 appears dispensable for most other AKT actions examined, indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments suggest brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. Evidence in mature brown adipocytes also suggests mTORC2 acts through ACLY to increase carbohydrate response element binding protein (ChREBP) activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis.

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“…Importantly, 55% of adipocytes in middle-aged MR EKO were larger than 3,000 mm 2 (Figure 4d). Despite the involvement of the crucial regulator of metabolism, mTOR, in controlling adipocyte cell size (Lee et al, 2017), we did not detect differences in the levels of phospho-mTOR among genotypes (data not shown). The fact that there was a trend toward increased cell size in 6-month and 11-month MR EKO mice relative to age-matched controls suggested that in MR EKO mice, the increased adipogenesis took place at earlier timepoints (Figure 4d).…”

Section: Middle-aged Mr Epidermal Knockout Skin Features Compartment-mentioning

confidence: 65%

Epidermal Mineralocorticoid Receptor Inactivation Affects the Homeostasis of All Skin Layers in Chronologically Aged Mice

Bigas

Sevilla

Pérez

2020

Journal of Investigative Dermatology

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The increased production of endogenous glucocorticoids (GCs) in the skin of the elderly population contributes to age-related defects strikingly similar to those occurring after pharmacologic treatments with GCs. GCs act through the ligand-dependent transcription factors GC receptor (GR) and mineralocorticoid receptor (MR). We reported that epidermal MR plays nonredundant roles relative to GR in adult mouse skin homeostasis; however, its relative contribution to natural skin aging has not been previously investigated. A 13-month-old MR epidermal knockout (MR EKO ) mice showed differential features of aging relative to controls (CO) in all skin compartments. MR EKO mice were resistant to age-induced epidermal atrophy but showed reduced dermal thickness, with decreased collagen deposition and decreased SMAD2 and 3 activity. Importantly, the dermal white adipose tissue (dWAT) was 2.5-fold enlarged in 13-month MR EKO versus CO, featuring adipocyte hyperplasia and hypertrophy at least in part through early increases in Pparg. These changes correlated with compartment-specific alterations in GC signaling. In addition, conditioned medium from MR EKO keratinocytes increased adipocyte differentiation, indicating paracrine regulation of adipogenesis through mechanisms that include activation of b-catenin signaling. These findings highlight the importance of epidermal MR in regulating cross-talk among skin compartments in naturally aged skin through GC and bcatenin signaling pathways.

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The Complex Roles of Mechanistic Target of Rapamycin in Adipocytes and Beyond

Cited by 53 publications

References 194 publications

MicroRNA-496 and Mechanistic Target of Rapamycin Expression are Associated with Type 2 Diabetes Mellitus and Obesity in Elderly People

MicroRNA-496 and Mechanistic Target of Rapamycin Expression are Associated with Type 2 Diabetes Mellitus and Obesity in Elderly People

mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis

Epidermal Mineralocorticoid Receptor Inactivation Affects the Homeostasis of All Skin Layers in Chronologically Aged Mice

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