Increased stability of phosphatase and tensin homolog by intermedin leading to scavenger receptor A inhibition of macrophages reduces atherosclerosis in apolipoprotein E-deficient mice

Dai, Xiaoyan; Cai, Yan; Mao, Ding-Ding; Qi, Yongfen; Tang, Chaoshu; Xu, Qingbo; Zhu, Yi; Xu, Mingjiang; Wang, Xian

doi:10.1016/j.yjmcc.2012.07.006

Cited by 51 publications

(39 citation statements)

References 41 publications

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“…macrophages after ADM2 treatment. It has been shown before that the CRLR-cAMP/PKA-pPTEN pathway is responsible for ADM2 inhibition of acetylated low-density lipoprotein uptake in macrophages (25), but the receptor and transduction signals involved in its M2 activation need to be addressed in the future. This study indicates that M2 macrophages also serve as a crucial contributor to the ADM2-mediated beiging effect in scWAT.…”

Section: Discussionmentioning

confidence: 99%

“…The drugs used for adipogenic differentiation were all purchased from Sigma-Aldrich (St. Louis, MO). Mouse peritoneal macrophages were isolated as described previously (25). Eight-week-old C57BL/6J male mice were injected intraperitoneally with 2 ml of 4% thioglycollate broth (BD Biosciences Clontech).…”

Section: Methodsmentioning

confidence: 99%

“…The homology of its mature peptide between rodents and humans is rather high (mouse versus rat, 97.9%; mouse versus human, 89.4%; human versus rat, 87.2%). ADM2 is ubiquitously expressed in various tissues, including adipose tissue (23,24), and has been reported to play protective roles in the cardiovascular and renal systems via multiple mechanisms, such as antiinflammation, inhibition of oxidative stress, and endoplasmic reticulum stress (25)(26)(27)(28). ADM2 can be synthesized and secreted from adipocytes, and its expression is down-regulated in adipose tissues of db/db mice and high-fat diet (HFD)-induced obese mice (29).…”

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confidence: 99%

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Adrenomedullin 2 Enhances Beiging in White Adipose Tissue Directly in an Adipocyte-autonomous Manner and Indirectly through Activation of M2 Macrophages

Zhang

Liang

et al. 2016

Journal of Biological Chemistry

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Adrenomedullin 2 (ADM2) is an endogenous bioactive peptide belonging to the calcitonin gene-related peptide family. Our previous studies showed that overexpression of ADM2 in mice reduced obesity and insulin resistance by increasing thermogenesis in brown adipose tissue. However, the effects of ADM2 in another type of thermogenic adipocyte, beige adipocytes, remain to be understood. The plasma ADM2 levels were inversely correlated with obesity in humans, and adipo-ADM2-transgenic (tg) mice displayed resistance to high-fat diet-induced obesity with increased energy expenditure. Beiging of subcutaneous white adipose tissues (WAT) was more noticeably induced in high-fat diet-fed transgenic mice with adipocyte-ADM2 overexpression (adipo-ADM2-tg mice) than in WT animals. ADM2 treatment in primary rat subcutaneous adipocytes induced beiging with up-regulation of UCP1 and beiging-related marker genes and increased mitochondrial uncoupling respiration, which was mainly mediated by activation of the calcitonin receptor-like receptor (CRLR)⅐receptor activitymodifying protein 1 (RAMP1) complex and PKA and p38 MAPK signaling pathways. Importantly, this adipocyte-autonomous beiging effect by ADM2 was translatable to human primary adipocytes. In addition, M2 macrophage activation also contributed to the beiging effects of ADM2 through catecholamine secretion. Therefore, our study reveals that ADM2 enhances subcutaneous WAT beiging via a direct effect by activating the CRLR⅐RAMP1-cAMP/PKA and p38 MAPK pathways in white adipocytes and via an indirect effect by stimulating alternative M2 polarization in macrophages. Through both mechanisms, beiging of WAT by ADM2 results in increased energy expenditure and reduced obesity, suggesting ADM2 as a novel anti-obesity target.An imbalance between energy intake and energy expenditure is the cause for the development of obesity, which is a high risk factor for type 2 diabetes and related metabolic disorders. Adaptive thermogenesis in adipose tissue is an important contributor to overall energy expenditure; thus, enhancing thermogenesis in adipose tissue is considered one of the promising therapeutic strategies to improve energy homeostasis (1).In contrast to white adipose tissue (WAT), 3 which stores energy as triglycerides, brown adipose tissue (BAT) dissipates energy as heat by uncoupling protein 1 (UCP1)-mediated uncoupling of the mitochondrial respiratory chain from ATP synthesis (2). Upon stimuli such as ␤-3 adrenergic agonists or cold challenge, some adipocytes within WAT can exhibit brown-like features (3, 4) and have been identified as the third type of adipocytes, named "brite" (brown-in-white) or "beige" adipocytes (5). This biological process is referred to as WAT "browning" or "beiging" (3).Studies in both rodents and humans indicated that beiging of WAT increases the whole-body metabolic rate and improves energy homeostasis in obesity and type 2 diabetes (3, 6 -10). Enhancing WAT beiging alone was sufficient to alleviate obesity in mice (6), and emerging evidence also sugges...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Adrenomedullin 2 Enhances Beiging in White Adipose Tissue Directly in an Adipocyte-autonomous Manner and Indirectly through Activation of M2 Macrophages

Zhang

Liang

et al. 2016

Journal of Biological Chemistry

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“…ADM2 has been shown to exert protective effects on cardiac ischemia/reperfusion injury, vascular calcification, and immunoglobulin A nephropathy by inhibiting inflammation, oxidative stress, and endoplasmic reticulum stress (12)(13)(14). We and other groups reported that ADM2 treatment reduced atherosclerosis by inhibiting foam cell formation and improving dyslipidemia (15)(16)(17). Recently, our group discovered that ADM2 had a protective effect on HFD-induced established obesity by increasing thermogenesis in adipocytes (18).…”

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confidence: 97%

Adrenomedullin 2 Improves Early Obesity-Induced Adipose Insulin Resistance by Inhibiting the Class II MHC in Adipocytes

Zhang

et al. 2016

Diabetes

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MHC class II (MHCII) antigen presentation in adipocytes was reported to trigger early adipose inflammation and insulin resistance. However, the benefits of MHCII inhibition in adipocytes remain largely unknown. Here, we showed that human plasma polypeptide adrenomedullin 2 (ADM2) levels were negatively correlated with HOMA of insulin resistance in obese human. Adipose-specific human ADM2 transgenic (aADM2-tg) mice were generated. The aADM2-tg mice displayed improvements in high-fat diet-induced early adipose insulin resistance. This was associated with increased insulin signaling and decreased systemic inflammation. ADM2 dose-dependently inhibited CIITA-induced MHCII expression by increasing Blimp1 expression in a CRLR/RAMP1-cAMP-dependent manner in cultured adipocytes. Furthermore, ADM2 treatment restored the high-fat diet-induced early insulin resistance in adipose tissue, mainly via inhibition of adipocyte MHCII antigen presentation and CD4 + T-cell activation. This study demonstrates that ADM2 is a promising candidate for the treatment of early obesity-induced insulin resistance.

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“…18 Human IMD gene encodes a prepropeptide of 148 amino acids with a signal peptide for secretion at the N terminus. IMD can be generated from prepro-IMD by proteolytic cleavage at Arg93-Arg94.…”

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Intermedin ₁₋ ₅₃ Attenuates Abdominal Aortic Aneurysm by Inhibiting Oxidative Stress

Jia

et al. 2016

ATVB

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Objective-Oxidative stress plays a critical role in the development of abdominal aortic aneurysm (AAA). Intermedin (IMD) is a regulator of oxidative stress. Here, we investigated whether IMD reduces AAA by inhibiting oxidative stress. Approach and Results-In angiotensin II-induced ApoE −/− mouse and CaCl 2 -induced C57BL/6J mouse model of AAA, IMD 1−53 significantly reduced the incidence of AAA and maximal aortic diameter. Ultrasonography, hematoxylin, and eosin staining and Verhoeff-van Gieson staining showed that IMD 1−53 significantly decreased the enlarged aortas and elastic lamina degradation induced by angiotensin II or CaCl 2 . Mechanistically, IMD 1−53 attenuated oxidative stress, inflammation, vascular smooth muscle cell apoptosis, and matrix metalloproteinase activation. IMD 1−53 inhibited the activation of redox-sensitive signaling pathways, decreased the mRNA and protein expression of nicotinamide adenine dinucleotide phosphate oxidase subunits, and reduced the activity of nicotinamide adenine dinucleotide phosphate oxidase in AAA mice. Expression of Nox4 was upregulated in human AAA segments and in angiotensin II-treated mouse aortas and was markedly decreased by IMD 1−53 . In vitro, vascular smooth muscle cells with small-interfering RNA knockdown of IMD showed significantly increased angiotensin II-induced reactive oxygen species, and small-interfering RNA knockdown of Nox4 markedly inhibited the reactive oxygen species. IMD knockdown further increased the apoptosis of vascular smooth muscle cells and inflammation, which was reversed by Nox4 knockdown. Preincubation with IMD 17−47 and protein kinase A inhibitor H89 inhibited the effect of IMD 1-53 , reducing Nox4 protein levels. Conclusions-IMD

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Increased stability of phosphatase and tensin homolog by intermedin leading to scavenger receptor A inhibition of macrophages reduces atherosclerosis in apolipoprotein E-deficient mice

Cited by 51 publications

References 41 publications

Adrenomedullin 2 Enhances Beiging in White Adipose Tissue Directly in an Adipocyte-autonomous Manner and Indirectly through Activation of M2 Macrophages

Adrenomedullin 2 Enhances Beiging in White Adipose Tissue Directly in an Adipocyte-autonomous Manner and Indirectly through Activation of M2 Macrophages

Adrenomedullin 2 Improves Early Obesity-Induced Adipose Insulin Resistance by Inhibiting the Class II MHC in Adipocytes

Intermedin ₁₋ ₅₃ Attenuates Abdominal Aortic Aneurysm by Inhibiting Oxidative Stress

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Increased stability of phosphatase and tensin homolog by intermedin leading to scavenger receptor A inhibition of macrophages reduces atherosclerosis in apolipoprotein E-deficient mice

Cited by 51 publications

References 41 publications

Adrenomedullin 2 Enhances Beiging in White Adipose Tissue Directly in an Adipocyte-autonomous Manner and Indirectly through Activation of M2 Macrophages

Adrenomedullin 2 Enhances Beiging in White Adipose Tissue Directly in an Adipocyte-autonomous Manner and Indirectly through Activation of M2 Macrophages

Adrenomedullin 2 Improves Early Obesity-Induced Adipose Insulin Resistance by Inhibiting the Class II MHC in Adipocytes

Intermedin 1− 53 Attenuates Abdominal Aortic Aneurysm by Inhibiting Oxidative Stress

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Intermedin ₁₋ ₅₃ Attenuates Abdominal Aortic Aneurysm by Inhibiting Oxidative Stress