Adrenomedullin 2 Enhances Beiging in White Adipose Tissue Directly in an Adipocyte-autonomous Manner and Indirectly through Activation of M2 Macrophages.
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)·receptor activity-modifying 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 CRLR·RAMP1-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.
From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
Ying
Y
Lv
From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
Song-Yang
SY
Zhang
From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
Xianyi
X
Liang
the Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
Heng
H
Zhang
the Department of General Surgery, Peking University Third Hospital, Beijing 100191, China, and.
Zhi
Z
Xu
From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
Bo
B
Liu
From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
Ming-Jiang
MJ
Xu
From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China, jiangchangtao@bjmu.edu.cn.
Changtao
C
Jiang
the Department of Cardiometabolic Disease, Merck Research Laboratories, Merck & Co, Inc., Kenilworth, New Jersey 07033 jin_shang@merck.com.
Jin
J
Shang
From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
Xian
X
Wang
D052438:Adipocytes, White / Q000276:immunology / Q000473:pathology; D002001:Adipose Tissue, Brown / Q000276:immunology* / Q000473:pathology; D052436:Adipose Tissue, White / Q000276:immunology* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000235:genetics / Q000276:immunology*; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D036361:Peptide Hormones / Q000235:genetics / Q000276:immunology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D022722:Thermogenesis; D015854:Up-Regulation
C484330:ADM2 protein, human; D009479:Neuropeptides; D036361:Peptide Hormones; C514552:intermedin protein, mouse
adipocyte; energy metabolism; macrophage; obesity; uncoupling protein