RalA controls glucose homeostasis by regulating glucose uptake in brown fat

Skorobogatko, Yuliya; Dragan, Morgan; Cordon, Claudia; Reilly, Shannon M.; Hung, Chao‐Wei; Xia, Wenmin; Zhao, Peng; Wallace, Martina; Lackey, Denise E.; Chen, Xiao Wei; Osborn, Olivia; Bogner‐Strauß, Juliane Gertrude; Theodorescu, Dan; Metallo, Christian M.; Olefsky, Jerrold M.; Saltiel, Alan R.

doi:10.1073/pnas.1801050115

Cited by 40 publications

(37 citation statements)

References 22 publications

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“…Surprisingly, MusMyD88 −/− had few muscle‐specific transcript changes when compared with Cre‐control. Only one transcript in muscle was significantly upregulated ( Igf1 ), while 5/9 downregulated transcripts ( Ip6k3, Ppargc1a, Ralgapa2, Gck, Trim63 ) in MusMyD88 −/− mice were associated with glucose homeostasis (Figure A‐7B). The most striking difference observed in muscle was decreased uncharacterized transcript 9930111J21Rik2 (2.9‐fold), which was also potently decreased (9‐fold) in visceral fat of MusMyD88 −/− (Figure B‐7C).…”

Section: Resultsmentioning

confidence: 99%

“…These were decreased expression of Ralgapa2 (muscle: ↓1.4‐fold; visceral fat: ↓1.8‐fold) and 9930111J21Rik2 (muscle: ↓2.9‐fold; visceral fat: ↓9.1‐fold), both of which were within the top 10 decreased genes, with 993011J21Rik2 being the most highly altered in both tissues. Lower expression of Ralgapa2 , an inhibitor of GLUT4 translocation , represents a mechanism by which absence of MyD88 in muscle may have prevented the inhibition of GLUT4 translocation that occurs with inactivity. Very little information is known about the gene 9930111J21Rik2 , but it appears to be immune related and regulated by interferon .…”

Section: Discussionmentioning

confidence: 99%

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Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity‐Induced Adiposity and Insulin Resistance

Mahmassani

Reidy

McKenzie

et al. 2020

Obesity

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Objective Inactivity and inflammation are linked to obesity and insulin resistance. It was hypothesized that MyD88 (mediates inflammation) knockout from muscle (MusMyD88−/−) would prevent, whereas miR146a−/− (MyD88 inhibitor) would exacerbate, inactivity‐induced metabolic disturbances. Methods Cre‐control, MusMyD88−/−, and miR146a−/− mice were given running wheels for 5 weeks to model an active phenotype. Afterward, half were placed into a small mouse cage (SMC) to restrict movement for 8 days. Body composition, muscle (3H)2‐deoxyglucose uptake, visceral fat histology, and tissue weight (hind limb muscles, visceral fat, and liver) were assessed. In skeletal muscle and visceral fat, RNA sequencing and mitochondrial function were performed on female MusMyD88−/− and Cre‐control SMC mice. Results The SMC induced adiposity, hyperinsulinemia, and muscle insulin‐stimulated glucose uptake, which was worsened in miR146a−/− mice. In females, MusMyD88−/− mice were protected. Female MusMyD88−/− mice during the SMC period (vs. Cre‐control) exhibited higher Igf1 and decreased Ip6k3 and Trim63 muscle expression. Visceral fat transcript changes corresponded to improved lipid metabolism, decreased adipose expansion (Gulp1↑, Anxa2↓, Ehd1↓) and meta‐inflammation (Hmox1↓), and increased beiging (Fgf10↑). Ralgapa2, negative regulator of GLUT4 translocation, and inflammation‐related gene 993011J21Rik2 were decreased in both muscle and fat. Conclusions Whole‐body miR146a−/− exacerbated inactivity‐induced fat gain and muscle insulin resistance, whereas MusMyD88−/− prevented insulin resistance in female mice.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity‐Induced Adiposity and Insulin Resistance

Mahmassani

Reidy

McKenzie

et al. 2020

Obesity

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“…It remains to be determined, however, whether Fndc5 mainly affects glucose tolerance and insulin sensitivity of the skeletal muscle or adipose tissues. Improvements in insulin sensitivity are associated with elevation of glucose transporter type 4 (Glut4) levels or Glut4 translocation to the cell membrane (63–65), and irisin induces Glut4 expression in myocytes and adipocytes (45, 46). It will be interesting to determine whether the blunted response to exercise‐induced improvements in insulin sensitivity in Fndc5 mutant mice is associated with lower levels of Glut4 expression because of a loss of irisin action on adipose or muscle tissues.…”

Section: Discussionmentioning

confidence: 99%

Fndc5 loss‐of‐function attenuates exercise‐induced browning of white adipose tissue in mice

Xiong

Zhang

et al. 2019

The FASEB Journal

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Fibronectin type III domain containing 5 (Fndc5) is a transmembrane protein highly expressed in the skeletal muscle. It was reported that exercise promotes the shedding of the extracellular domain of Fndc5, generating a circulating peptide (irisin) that cross‐talks to adipose tissues to convert lipid‐storing white adipocytes to energy‐catabolizing beige adipocytes. However, the requirement of Fndc5 in mediating the beneficial effect of exercise remains to be determined. Here, we created a mouse model of Fndc5 mutation through transcription activator–like effector nuclease–mediated DNA targeting. The Fndc5 mutant mice have normal skeletal muscle development, growth, regeneration, as well as glucose and lipid metabolism at resting state, even when fed a high‐fat diet. In response to running exercise, however, the Fndc5 mutant mice exhibit reduced glucose tolerance and insulin sensitivity and have lower maximal oxygen consumption compared with the exercised wild‐type mice. Mechanistically, Fndc5 mutation attenuates exercise‐induced browning of white adipose tissue that is crucial for the metabolic benefits of physical activities. These data provide genetic evidence that Fndc5 is dispensable for muscle development and basal metabolism but essential for exercise‐induced browning of white adipose tissues in mice.—Xiong, Y., Wu, Z., Zhang, B., Wang, C., Mao, F., Liu, X., Hu, K., Sun, X., Jin, W., Kuang, S. Fndc5 loss‐of‐function attenuates exercise‐induced browning of white adipose tissue in mice. FASEB J. 33, 5876–5886 (2019).http://www.fasebj.org

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“…Due to the high affinity of the guanine nucleotides at their binding sites, small GTPases such as RAS and RAL are hard to target pharmacologically, however. Whereas to date, no clinically suitable RAS inhibitors are available, 1 , 4 , 56 a small molecule RAL inhibitor has recently been described, 41 showing in vitro effects in adipose tissue 57 and in chronic myelogenous leukemia. 58 This allosteric compound has been developed to stabilize RAL in its inactive GDP-bound state and thus prevent its activation.…”

Section: Discussionmentioning

confidence: 99%

RAL GTPases mediate multiple myeloma cell survival and are activated independently of oncogenic RAS

et al. 2019

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Oncogenic RAS provides crucial survival signaling for up to half of multiple myeloma cases, but has so far remained a clinically undruggable target. RAL is a member of the RAS superfamily of small GTPases and is considered to be a potential mediator of oncogenic RAS signaling. In primary multiple myeloma, we found RAL to be overexpressed in the vast majority of samples when compared with pre-malignant monoclonal gammopathy of undetermined significance or normal plasma cells. We analyzed the functional effects of RAL abrogation in myeloma cell lines and found that RAL is a critical mediator of survival. RNAi-mediated knockdown of RAL resulted in rapid induction of tumor cell death, an effect which was independent from signaling via mitogen-activated protein kinase, but appears to be partially dependent on Akt activity. Notably, RAL activation was not correlated with the presence of activating RAS mutations and remained unaffected by knockdown of oncogenic RAS. Furthermore, transcriptome analysis yielded distinct RNA expression signatures after knockdown of either RAS or RAL. Combining RAL depletion with clinically relevant anti-myeloma agents led to enhanced rates of cell death. Our data demonstrate that RAL promotes multiple myeloma cell survival independently of oncogenic RAS and, thus, this pathway represents a potential therapeutic target in its own right.

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RalA controls glucose homeostasis by regulating glucose uptake in brown fat

Cited by 40 publications

References 22 publications

Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity‐Induced Adiposity and Insulin Resistance

Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity‐Induced Adiposity and Insulin Resistance

Fndc5 loss‐of‐function attenuates exercise‐induced browning of white adipose tissue in mice

RAL GTPases mediate multiple myeloma cell survival and are activated independently of oncogenic RAS

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