Carbon monoxide–induced metabolic switch in adipocytes improves insulin resistance in obese mice

Braud, Laura; Pini, Maria Silvia; Muchová, Lucie; Manin, Sylvie; Kitagishi, Hiroaki; Sawaki, Daigo; Czibik, Gabor; Ternacle, Julien; Dérumeaux, Geneviève; Foresti, Roberta; Motterlini, Roberto

doi:10.1172/jci.insight.123485

Cited by 44 publications

(35 citation statements)

References 47 publications

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“…Finally, the results obtained with HYCO‐6 clearly showed that the in vitro Hb or myoglobin assays are not sufficient for determining the ability of a CO‐RM (hybridized or not) to deliver CO to cells or tissues. In view of this work, and as recently reported, any satisfactory characterization of a CO‐based therapeutic agent clearly requires the combined assessment of CO release in vitro (myoglobin or Hb assay) and CO accumulation in cells (COP‐1 or hemoCD assay).…”

Section: Discussionmentioning

confidence: 82%

Design and Biological Evaluation of Manganese‐ and Ruthenium‐Based Hybrid CO‐RMs (HYCOs)

et al. 2019

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Interest in the therapeutic effects of carbon monoxide (CO), a product of heme degradation catalyzed by the enzyme heme oxygenase‐1 (HO‐1), has led to the development of CO‐releasing molecules (CO‐RMs) for the controlled delivery of this gas in vivo. We recently proposed conjugating a cobalt‐based CO‐RM with various activators of nuclear factor erythroid 2‐related factor 2 (Nrf2), the transcription factor that regulates HO‐1 expression, in order to exploit the beneficial effects of exogenous and endogenous CO. In this study, we describe the preparation of hybrid molecules (termed HYCOs) conjugating a fumaric acid derivative as an Nrf2 activator to a Mn‐ or a Ru‐based CO‐RM known to be pharmacologically active. With the exception of an acyl‐manganese complex, these hybrids were obtained by associating the two bioactive entities by means of a linker of variable structure. X‐ray diffraction analyses and preliminary biological investigations are also presented.

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Section: Discussionmentioning

confidence: 82%

Design and Biological Evaluation of Manganese‐ and Ruthenium‐Based Hybrid CO‐RMs (HYCOs)

et al. 2019

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“…Another important result in this study is that either HO-1 induction or CO interferes with the uptake of LDL and glucose in 3T3L1 cells. There have been considerable numbers of experimental data showing that obesity is suppressed by the induction of HO or by the administration of CO-RM [54][55][56][57] . However, reception mechanisms of CO and mechanisms by which CO suppresses obesity remained largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Progesterone receptor membrane associated component 1 enhances obesity progression in mice by facilitating lipid accumulation in adipocytes

et al. 2020

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Progesterone receptor membrane associated component 1 (PGRMC1) exhibits haemdependent dimerization on cell membrane and binds to EGF receptor and cytochromes P450 to regulate cancer proliferation and chemoresistance. However, its physiological functions remain unknown. Herein, we demonstrate that PGRMC1 is required for adipogenesis, and its expression is significantly enhanced by insulin or thiazolidine, an agonist for PPARγ. The haem-dimerized PGRMC1 interacts with low-density lipoprotein receptors (VLDL-R and LDL-R) or GLUT4 to regulate their translocation to the plasma membrane, facilitating lipid uptake and accumulation, and de-novo fatty acid synthesis in adipocytes. These events are cancelled by CO through interfering with PGRMC1 dimerization. PGRMC1 expression in mouse adipose tissues is enhanced during obesity induced by a high fat diet. Furthermore, adipose tissue-specific PGRMC1 knockout in mice dramatically suppressed high-fat-diet induced adipocyte hypertrophy. Our results indicate a pivotal role of PGRMC1 in developing obesity through its metabolic regulation of lipids and carbohydrates in adipocytes.

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“…Elevated ferritin for iron stores is positively associated with the prevalence of metabolic syndrome and with insulin resistance [ 11 ]. Carbon monoxide induces metabolic switch in adipocytes and reduces insulin resistance in obese mice [ 12 ]. Administration of hemin, an HO-1 inducer, protects against streptozotocin-induced increase in blood glucose in rats [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Heme Oxygenase 1 and 2 Differentially Regulate Glucose Metabolism and Adipose Tissue Mitochondrial Respiration: Implications for Metabolic Dysregulation

Yao

Peterson

et al. 2020

IJMS

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Heme oxygenase (HO) consists of inducible (HO-1) and constitutive (HO-2) isoforms that are encoded by Hmox1 and Hmox2 genes, respectively. As an anti-inflammatory and antioxidant molecule, HO participates in the development of metabolic diseases. Whether Hmox deficiency causes metabolic abnormalities under basal conditions remains unclear. We hypothesized that HO-1 and HO-2 differentially affect global and adipose tissue metabolism. To test this hypothesis, we determined insulin sensitivity, glucose tolerance, energy expenditure, and respiratory exchange ratio in global Hmox1-/- and Hmox2-/- mice. Body weight was reduced in female but not male Hmox1-/- and Hmox2-/- mice. Reduced insulin sensitivity and physical activity were observed in Hmox1-/- but not Hmox2-/- mice. Deletion of either Hmox1 or Hmox2 had no effects on glucose tolerance, energy expenditure or respiratory exchange ratio. Mitochondrial respiration was unchanged in gonadal fat pads (white adipose tissue, WAT) of Hmox1-/- mice. Hmox2 deletion increased proton leak and glycolysis in gonadal, but not interscapular fat tissues (brown adipose tissue, BAT). Uncoupling protein and Hmox1 genes were unchanged in gonadal fat pads of Hmox2-/- mice. Conclusively, HO-1 maintains insulin sensitivity, while HO-2 represses glycolysis and proton leak in the WAT under basal condition. This suggests that HO-1 and HO-2 differentially modulate metabolism, which may impact the metabolic syndrome.

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Carbon monoxide–induced metabolic switch in adipocytes improves insulin resistance in obese mice

Cited by 44 publications

References 47 publications

Design and Biological Evaluation of Manganese‐ and Ruthenium‐Based Hybrid CO‐RMs (HYCOs)

Design and Biological Evaluation of Manganese‐ and Ruthenium‐Based Hybrid CO‐RMs (HYCOs)

Progesterone receptor membrane associated component 1 enhances obesity progression in mice by facilitating lipid accumulation in adipocytes

Heme Oxygenase 1 and 2 Differentially Regulate Glucose Metabolism and Adipose Tissue Mitochondrial Respiration: Implications for Metabolic Dysregulation

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