Ablation of LMO4 in glutamatergic neurons impairs leptin control of fat metabolism

Zhou, Xun; Gomez-Smith, Mariana; Qin, Zhaohong; Duquette, Philippe M.; Cárdenas-Blanco, Arturo; Punarpreet, S.; Harper, Mary‐Ellen; Tsai, Eve C.; Anisman, Hymie; Chen, Hsiao‐Huei

doi:10.1007/s00018-011-0794-3

Cited by 24 publications

(19 citation statements)

References 47 publications

(68 reference statements)

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“…Recently, LMO4 has been proved to be a novel modulator of leptin signaling in the hypothalamus and to regulate fat metabolism [27]. Together with our findings, these data suggest that LMO4 regulates energy homeostasis and fat metabolism at different levels and that LMO4 may be a potential targetfor future therapy for obesity.…”

Section: Discussionsupporting

confidence: 80%

LMO4 modulates proliferation and differentiation of 3T3‐L1 preadipocytes

Wang

Shi

et al. 2013

FEBS Letters

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Edited by Laszlo NagyKeywords: LMO4 3T3-L1 preadipocyte Cell proliferation Preadipocyte differentiation a b s t r a c t Previous microarray analyses revealed that LMO4 is expressed in 3T3-L1 preadipocytes, however, its roles in adipogenesis are unknown. In the present study, using RT-PCR sequencing and quantitative real-time RT-PCR, we confirmed that LMO4 gene is expressed in 3T3-L1 preadipocytes and its expression peaks at the early stage of 3T3-L1 preadipocyte differentiation. Further analyses showed that LMO4 knockdown decreased the proliferation of 3T3-L1 preadipocytes, and attenuated the differentiation of 3T3-L1 preadipocytes, as evidenced by reduced lipid accumulation and down-regulation of PPARc gene expression. Collectively, our findings indicate that LMO4 is a novel modulator of adipogenesis.

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Section: Discussionsupporting

confidence: 80%

LMO4 modulates proliferation and differentiation of 3T3‐L1 preadipocytes

Wang

Shi

et al. 2013

FEBS Letters

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“…Later studies reported that LMO4 is also present in the cytoplasm and interacts with membrane-bound receptors and kinases to regulate cellular functions in response to extracellular signals (Novotny-Diermayr et al, 2005;Bong et al, 2007;Chen et al, 2007b;Schaffar et al, 2008;Schock et al, 2008;Zhou et al, 2012). Our previous studies showed that subcellular localization and cytoplasmic/nuclear shuttling of LMO4 is dynamically regulated by stresses and extracellular signals (Chen et al, 2007b).…”

Section: Discussionmentioning

confidence: 99%

“…All procedures were approved by the animal care and use committee of the University of Ottawa (Ottawa, Ontario, Canada). LMO4KO mice (CaMK2␣Cre/LMO4flox mice) were bred in a CD1 background as described previously (Schock et al, 2008;Qin et al, 2012;Zhou et al, 2012). HFD consisted of 60% kilocalories from fat (TD.06414 Adjusted Calories Diet; Harlan Laboratories) fed to the mice starting at 2 months of age for 7 d. In all studies, male mice were used.…”

Section: Methodsmentioning

confidence: 99%

The LIM Domain Only 4 Protein Is a Metabolic Responsive Inhibitor of Protein Tyrosine Phosphatase 1B That Controls Hypothalamic Leptin Signaling

Pandey

Zhou

Qin

et al. 2013

Journal of Neuroscience

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Protein tyrosine phosphatase 1B (PTP1B) counteracts leptin signaling and is a therapeutic target for obesity and diabetes. Here we found that LIM domain only 4 (LMO4) inhibits PTP1B activity by increasing the oxidized inactive form of PTP1B. Mice with neuronal ablation of LMO4 have elevated PTP1B activity and impaired hypothalamic leptin signaling, and a PTP1B inhibitor normalized PTP1B activity and restored leptin control of circulating insulin levels. LMO4 is palmitoylated at its C-terminal cysteine, and deletion of this residue prevented palmitoylation and retention of LMO4 at the endoplasmic reticulum and abolished its inhibitory effect on PTP1B. Importantly, LMO4 palmitoylation is sensitive to metabolic stress; mice challenged with a brief high-fat diet or acute intracerebroventricular infusion of saturated fatty acid had less palmitoylated LMO4, less oxidized PTP1B, and increased PTP1B activity in the hypothalamus. Thus, unleashed PTP1B activity attributable to loss of LMO4 palmitoylation may account for rapid loss of central leptin signaling after acute exposure to saturated fat.

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“…LMO4 KO and LMO4 flox littermate mice were genotyped and maintained on a CD-1 background as described previously (Schock et al, 2008;Zhou et al, 2012). CamK2␣Cre/ LMO4 flox mice and age-matched CamK2␣Cre/(LMO4 flox/Ϫ ) (LMO4 Het) or LMO4 flox / flox (WT) controls were used in all experiments.…”

Section: Methodsmentioning

confidence: 99%

LIM Domain Only 4 (LMO4) Regulates Calcium-Induced Calcium Release and Synaptic Plasticity in the Hippocampus

Qin¹,

Zhou²,

Gomez-Smith³

et al. 2012

J. Neurosci.

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The LIM domain only 4 (LMO4) transcription cofactor activates gene expression in neurons and regulates key aspects of network formation, but the mechanisms are poorly understood. Here, we show that LMO4 positively regulates ryanodine receptor type 2 (RyR2) expression, thereby suggesting that LMO4 regulates calcium-induced calcium release (CICR) in central neurons. We found that CICR modulation of the afterhyperpolarization in CA3 neurons from mice carrying a forebrain-specific deletion of LMO4 (LMO4 KO) was severely compromised but could be restored by single-cell overexpression of LMO4. In line with these findings, two-photon calcium imaging experiments showed that the potentiation of RyR-mediated calcium release from internal stores by caffeine was absent in LMO4 KO neurons. The overall facilitatory effect of CICR on glutamate release induced during trains of action potentials was likewise defective in LMO4 KO, confirming that CICR machinery is severely compromised in these neurons. Moreover, the magnitude of CA3-CA1 longterm potentiation was reduced in LMO4 KO mice, a defect that appears to be secondary to an overall reduced glutamate release probability. These cellular phenotypes in LMO4 KO mice were accompanied with deficits in hippocampus-dependent spatial learning as determined by the Morris water maze test. Thus, our results establish LMO4 as a key regulator of CICR in central neurons, providing a mechanism for LMO4 to modulate a wide range of neuronal functions and behavior.

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Ablation of LMO4 in glutamatergic neurons impairs leptin control of fat metabolism

Cited by 24 publications

References 47 publications

LMO4 modulates proliferation and differentiation of 3T3‐L1 preadipocytes

LMO4 modulates proliferation and differentiation of 3T3‐L1 preadipocytes

The LIM Domain Only 4 Protein Is a Metabolic Responsive Inhibitor of Protein Tyrosine Phosphatase 1B That Controls Hypothalamic Leptin Signaling

LIM Domain Only 4 (LMO4) Regulates Calcium-Induced Calcium Release and Synaptic Plasticity in the Hippocampus

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