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Adenylate Cyclase 3: a New Target for Anti‐Obesity Drug Development

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Adenylate Cyclase 3: a New Target for Anti‐Obesity Drug Development obesity reviews doi: 10.1111/obr.12430 Obesity Pharmacotherapy Adenylate cyclase 3: a new target for anti-obesity drug development L. Wu,1 C. Shen,2 M. Seed Ahmed,3 C.-G. Östenson4 and H. F. Gu5,6 1Jiangsu Key Laboratory of Drug Screening, Summary China Pharmaceutical University, Nanjing Obesity has become epidemic worldwide, and abdominal obesity has a negative im- 210009, China, 2Department of Epidemiology, pact on health. Current treatment options on obesity, however, still remain limited. School of Public Health, Nanjing Medical It is then of importance to find a new target for anti-obesity drug development University, Nanjing 211166, China, 3Unit for based upon recent molecular studies in obesity. Adenylate cyclase 3 (ADCY3) is Medical Education, Centre for Learning and the third member of adenylyl cyclase family and catalyses the synthesis of cAMP Knowledge, Department of Learning, from ATP. Genetic studies with candidate gene and genome-wide association study Informatics, Management and Ethics, approaches have demonstrated that ADCY3 genetic polymorphisms are associated Karolinska Institutet, Stockholm 17177, with obesity in European and Chinese populations. Epigenetic studies have indi- Sweden, 4Rolf Luft Center for Diabetes cated that increased DNA methylation levels in the ADCY3 gene are involved in Research and Endocrinology, Department of the pathogenesis of obesity. Furthermore, biological analyses with animal models Molecular Medicine and Surgery, Karolinska have implicated that ADCY3 dysfunction resulted in increased body weight and Institutet, Karolinska University Hospital, Solna, fat mass, while reduction of body weight is partially explained by ADCY3 activa- Stockholm 17176, Sweden, 5Department of tion. In this review, we describe genomic and biological features of ADCY3, sum- Clinical Science, Intervention and marize genetic and epigenetic association studies of the ADCY3 gene with obesity Technologies, Karolinska Institutet, Karolinska and discuss dysfunction and activation of ADCY3. Based upon all data, we suggest University Hospital, Huddinge, Stockholm that ADCY3 is a new target for anti-obesity drug development. Further investiga- 14157, Sweden, and 6Center of Molecular tion on the effectiveness of ADCY3 activator and its delivery approach to treat ab- Medicine, Karolinska Institutet, Karolinska dominal obesity has been taken into our consideration. University Hospital, Solna, Stockholm 17176, Sweden Keywords: Adenylate cyclase 3, body mass index, obesity. Received 15 March 2016; revised 6 April 2016; Abbreviations: ADCY3, adenylate cyclase 3; ATP, adenosine triphosphate; BMI, accepted 19 April 2016 body mass index; cAMP, 3’,5’-cyclic adenosine monophosphate; CNS, central ner- vous system; GK, Goto–Kakizaki; GWAS, genome-wide association study; T2D, Address for correspondence: HF Gu, type 2 diabetes; UTR, untranslated region. Department of Clinical Science, Intervention and Technologies, Karolinska Institutet, obesity reviews (2016) 17, 907–914 Karolinska University Hospital, Huddinge, Stockholm 14157, Sweden. E-mail: [email protected] Introduction more than 1.9 billion adults (39% of populations) are over- weight. Of them over 600 million (13%) are obese. More- Obesity has become a large and fast growing public health over, 42 million children under the age of 5 years old are problem in the world. Since 1980, the prevalence of obesity obese or overweight (1–4). Obesity and particularly abdom- has more than doubled. According to the reports in 2014, inal obesity (also known as central obesity) are widely 907 © 2016 World Obesity 17, 907–914, September 2016 908 ADCY3 and anti-obesity L. Wu et al. obesity reviews recognized as the major risk factors for non-communicable Table 1 Bio-informatics of adenylate cyclase 3 diseases, such as cardiovascular diseases (mainly heart dis- Alliases Adenylate cyclase, olfactive type; adenylate cyclase ease and stroke), diabetes (mainly type 2), musculoskeletal type III; ATP pyrophosphate-lyase 3; adenylyl disorders (especially osteoarthritis), cancers (endometrial, cyclase 3; EC 4.6.1.1; AC-III; AC3; ADCY3 prostate, breast and colon), reproductive dysfunction, liver External IDs HGNC: 234; Entrez gene: 109; Ensembl: – ENSG00000138031; OMIM:600291; UniProtKB: and kidney diseases (4 7). Although diet, exercise and be- O60266 havioural modification have been used as obesity manage- Type Olfactive and sensitive to Ca2+–calmodulin ment approaches, drugs may amplify the adherence to Chromosomal 2p23.3 behaviour change and improve physical function (8). In localization some patients, the treatment with dieting and physical exer- Genomic DNA NC_000002.12; NT_022184.16; NC_018913.2 mRNA NM_004036 cise is not a viable option. For these patients, anti-obesity miRNA regulation Has-miR-128; Has-miR-27a drugs can be a better alternative. Current anti-obesity drug Post-translational Ubiquitination at Lys1046, Lys1111 and Lys1120 candidates have aimed to reduce food intake by either curb- modifications NX_O06266 ing appetite or suppressing the craving for food or reducing Glycosylation at Asn736 NX_O06266 fi the gastro-intestinal digestion of nutrients, e.g., lipids Modi cation sites at PhosphoSitePlus O06266 Protein details NP_004027.2; 1,144 AA/128,960 Da (9,10). However, several of these agents have been associ- Belongs to the adenylyl cyclase class-4/guanylyl ated with severe psychiatric and/or cardiovascular side cyclase family effects, highlighting the necessity to discover and develop Contains 2 guanylate cyclase domains the new anti-obesity drugs. Biological function Activated by calcium/calmodulin Adenylyl cyclases (ADCYs) are enzymes that catalyse the Mediates odorant detection (possibly) via modulation ’ ’ of intracellular cAMP concentration synthesis of 3 ,5 -cyclic adenosine monophosphate (cAMP) Expressed in olfactory sensory neurons, brain, spinal from adenosine triphosphate (ATP). cAMP is a second mes- and retina, striatum and hypothalamus, heart, lung, senger and used for intracellular signal transduction. This kidney, liver, pancreas, placenta, skeletal muscle, messenger is associated with function of kinases in several adipocyte biochemical processes, including the regulation of carbohy- Diseases Obesity; thyroid adenoma; precocious puberty associated drate, and lipid metabolism. In the family of ADCYs, there are 10 closely related members, including ADCY1-9 and ADCY-activating polypeptide 1. All these ADCY1-9 are polymorphisms have been included into genetic association located on the inner side of the plasma membrane, anchored studies (16–21). In the ADCY3 gene promoter region, there at various locations in the interior of the cell and widely are 10 binding sites for transcription factors, including expressed in most organs and cell types in the body (11– FOXO4, Ik-2, Oct.B1, Oct-B2, Oct-B3, POU2F1a, 13). Interestingly, an important paralog of ADCY3 is POU2F2, POU2F1, POU2F2C and POU2F2B. Particularly, ADCY5, the fifth member in the same family. The ADCY5 there are two CpG islands (cg16888658 and cg17644208) genetic polymorphisms have been recently found to be asso- that have been selected for DNA methylation analysis ciated with type 2 diabetes (T2D) but not obesity. Dupuis (22,23). ADCY3 protein has 1,144 amino acids, and its mo- et al. have reported that the ADCY5 genetic polymorphism lecular weight is 128,960 Da. This protein is membrane rs11708067 is associated with elevate fasting glucose levels bound and Ca2+–calmodulin sensitive (12). According to and surrogate estimate of beta-cell function (HOMA-B) in the previous reports, ADCY3 is expressed in olfactory sen- the patients with T2D (14). Andersson et al. have demon- sory neurons, brain, spinal and retina, heart, lung, kidney, strated that this polymorphism is inversely associated with liver, pancreas, placenta and skeletal muscle. Recent studies birth weight in T2D (15). In this review, we summarize ge- with animal models have demonstrated that ADCY3 is pre- netic and epigenetic association studies of the ADCY3 gene sented in the certain regions of the brain, including striatum in obesity, interpret the results from biological experiments and hypothalamus (suprachiasmatic, paraventricular, ventro- with animal models and finally discuss the possibility of medial and arcuate nucleus) and adipocyte tissues (24,25). ADCY3-targeted therapies to treat abdominal obesity. Moreover, there are two micro-RNAs Has-miR-128 and Has-miR-27a, which may be included in the regulation of ADCY3 expression in addition to transcription binding Genomic and biological features of ADCY3 factors and DNA methylation alteration in the promoter. Adenylate cyclase 3 is the third family member of adenylyl cyclases, and its genomic and biological features are sum- Genetic and epigenetic studies of ADCY3 in marized in Table 1. The ADCY3 gene is located in chromo- obesity some 2p23.3 and consists of 21 exons with large 5’- and 3’- UTRs. In the ADCY3 gene sequence, one non-synonymous In 2008, we reported the first genetic association study of (rs1167272, Ser107Pro) and several intronic ADCY3 in Swedish subjects with T2D and obesity (16). 17, 907–914, September 2016 © 2016 World Obesity obesity reviews ADCY3 and anti-obesity L. Wu et al. 909 The original hypothesis of our study was created based whole genome. In the recent years, four GWASs have repli- upon the results from experiments with Goto–Kakizaki cated the genetic association between ADCY3 and obesity (GK) rats in our laboratory (24). GK rat is an animal model in European populations
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