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Free PDF Download European Review for Medical and Pharmacological Sciences 2019; 23: 1357-1378 Mendelian obesity, molecular pathways and pharmacological therapies: a review S. PAOLACCI1, A. BORRELLI2, L. STUPPIA3, F.C. CAMPANILE4, T. DALLAVILLA1, J. KRAJČOVIČ5, D. VESELENYIOVA5, T. BECCARI6, V. UNFER7, M. BERTELLI8; GENEOB PROJECT 1MAGI’S Lab, Genetic Testing Laboratory, Rovereto (TN), Italy 2Obesity Center, Pineta Grande Hospital, Castelvolturno (CE), Italy 3Department of Psychological Sciences, Health and Territory, University “G. d’Annunzio”, Chieti-Pescara, Italy 4Department of Surgery, San Giovanni Decollato Andosilla Hospital, ASL VT, Civita Castellana, Italy 5Department of Biology, Faculty of Natural Sciences, University of ss. Cyril and Methodius, Trnava, Slovakia 6Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy 7Department of Developmental and Social Psychology, Faculty of Medicine and Psychology, Sapienza, University of Rome, Rome, Italy 8MAGI Euregio, Nonprofit Genetic Testing Laboratory, Bolzano, Italy Abstract. – OBJECTIVE: In this qualitative re- Introduction view we analyze the major pathways and mecha- nisms involved in the onset of genetically-deter- Adipocytes are the major constituents of whi- mined obesity (Mendelian obesity), identifying te adipose tissue. They control energy balance by possible pharmacological treatments and trials. MATERIALS AND METHODS: We searched storing and mobilizing triacylglycerol, and they PubMed with the keywords (obesity[Title/Ab- play roles in endocrine and paracrine regulation. stract]) AND mutation[Title/Abstract], and OMIM Adipose tissue controls glucose metabolism, ap- with the keyword “obesity”. In both cases, we petite, immunological and inflammatory respon- selected non-syndromic Mendelian obesity. We ses, angiogenesis, blood pressure, and reproducti- then searched ClinicalTrials.gov with the follow- ve function through many specific factors. When ing criteria: “recruitment status: active, not re- adipocytes accumulate, they form adipose tissue. cruiting and completed”; “study type: interven- tional (clinical trial)”; “study results: with re- The amount of adipose tissue in the body is mainly sults”; type of intervention: “drug or dietary regulated by leptin, a hormone produced by adi- supplement”. pocytes themselves. Adipose tissue expands when RESULTS: From the PubMed and OMIM search- the number and size of adipocytes increases1. An es we obtained a total of 15 genes associated excessive amount or size of adipocytes can gene- with monogenic Mendelian obesity. From Clini- rate a morbid condition called obesity. Obesity is calTrials.gov we retrieved 46 completed or active trials of pharmacological treatments. highly heritable and arises from the interplay of CONCLUSIONS: We summarized the molecu- many genes and environmental factors. It is de- lar bases of Mendelian obesity and searched for fined as resulting from a prolonged imbalance any clinical trials completed or underway for the between calorie intake and energy utilization. An treatment of severe forms of obesity. Most Men- understanding of how these variations influence delian obesities are linked to dysfunctions in susceptibility to become or remain obese will ho- the leptin/melanocortin signaling pathway, and pefully provide insights into how obesity occurs most of the possible drugs target this pathway 2 in order to improve energy expenditure and re- and how to prevent and treat it . It is important to duce food intake. note that about 5% of cases of obesity are mono- genic3. Most mutant genes in Mendelian obesity Key Words: are also involved in a predisposition for common Mendelian obesity, Leptin/melanocortin pathway, obesity through the action of common single nu- Adipogenesis, Clinical trials. cleotide polymorphisms (SNPs) (minor allele fre- Corresponding Author: Stefano Paolacci, MD; email: [email protected] 1357 S. Paolacci, A. Borrelli, L. Stuppia, F.C. Campanile, T. Dallavilla, et al. quency >1%). In this qualitative review, we clarify The Leptin/Melanocortin Pathway and analyze the major pathways and mechanisms Leptin (LEP) is secreted by adipose tissue and involved in the onset of genetically-determined binds to leptin receptors (LEPR) in the hypotha- obesity (Mendelian obesity). We also review dru- lamus, where it controls food intake through the gs that may be or are already used to treat obesity. melanocortin pathway. Leptin acts in the arcuate nucleus where it activates neurons that express the anorexigenic peptides pro-opiomelanocortin Materials and Methods (POMC), as well as cocaine- and amphetami- ne-related transcript preprotein (CARTPT) deri- To identify genes involved in isolated mono- vatives that control food intake. Leptin also has genic obesity we searched articles published in inhibitory effects on the neurons that express the English up to October 2018 in PubMed with the orexigenic peptides neuropeptide Y (NPY) and following combination of terms: (obesity[Title/ Agouti-related protein (AGRP), which increa- Abstract]) AND mutation[Title/Abstract], where- se food intake. Both POMC/CARTPT and NPY/ as in OMIM we searched using the word: “obesi- AGRP subsets of neurons have many connections ty”. From the records retrieved, we only selected with other hypothalamic nuclei. The binding of publications dealing with Mendelian non-syn- leptin to its receptor initiates a cascade of signal dromic obesity. We only considered disorders transduction pathways, deficits of which may cau- for which the pathogenicity of the mutations was se leptin resistance. With the help of Src homolo- supported by segregation studies in more than gy 2B adapter protein 1 (SH2B1), LEPR recruits one multigenerational family and/or by functio- JAK2, which in turn phosphorylates the intracel- nal studies. To find drugs useful to treat obesity lular domain of LEPR. The phosphorylated in- we searched ClinicalTrials.gov with the following tracellular domain of LEPR binds and activates criteria: “recruitment status: active, not recrui- STAT3, which with the aid of Tubby bipartite tran- ting, and completed”; “study type: interventional scription factor (TUB), translocates to the nucleus (clinical trial)”; “study results: with results”; type and acts as a transcription factor, mediating the of intervention “drug or dietary supplement”. anorexigenic effects of leptin4. Besides the JAK/ From the list obtained, we selected drugs that STAT pathway, another important intracellular were used to treat obesity, excluding drugs used pathway for energy homeostasis is the PI3K pa- only to treat obesity-related complications. thway. Indeed, LEPR stimulation mediates tyrosi- ne phosphorylation of IRS proteins by JAK2. IRS in turn activates PI3K that generates phosphati- Results dylinositol-3,4,5-trisphosphate (PIP3) from pho- sphatidylinositol-4,5-bisphosphate (PIP2). The From the PubMed and OMIM searches, we importance of this pathway in the regulation of obtained 1878 and 655 entries, respectively, from energy balance is highlighted by the fact that ad- which we extracted a total of 15 genes associated ministration of myo-inositol (the core constituent with monogenic Mendelian non-syndromic obe- of PIP) may improve endocrine and metabolic pa- sity. From ClinicalTrials.gov we retrieved a total rameters, and reduce BMI in overweight patients 5 of 433 entries and as described in “Methods”, we with polycystic ovary syndrome . PIP3 induces selected 46 completed or active trials of pharma- activation of PDK1 that triggers a cascade inclu- cological treatments. ding Akt and members of the PKC family. Akt activates mTOR and inhibits the transcription factor FOXO16. Note the close interaction betwe- Mendelian Monogenic Obesity en STAT3 and FOXO1, both of which bind AGRP and POMC promoters. While STAT3 inhibits Most genes known to be associated with mo- expression of AGRP and activates expression of nogenic obesity are related to the leptin/melano- POMC, FOXO1 has the opposite effect6. cortin pathway (Figure 1) and are expressed in the After its synthesis, POMC is cleaved by hypothalamus. They code for proteins involved in prohormone convertase 1 and 2 (PC1/2) and by food intake/energy expenditure balance. Another carboxypeptidase E (CPE), which are expressed pathway associated with obesity leads to the for- in the feeding centers of the ARC, to yield mela- mation of mature white adipose tissue and invol- nocortins α-, β- and γ-MSH. The actions of me- ves several growth and transcription factors. lanocortins are mediated by two G-protein cou- 1358 Mendelian obesity, molecular pathways and pharmacological therapies: a review pled receptors known as melanocortin 3 and 4 culating leptin (LEP) binds to the leptin receptor receptors (MC3R, MC4R) that play a central role (LEPR) in the hypothalamus, which activates in the control of body weight, decreasing food downstream signaling pathways that inhibit fee- intake and favoring weight loss6. Melanocortin ding and promote energy expenditure. Consistent- 2 receptor accessory protein 2 (MRAP2) can re- ly, loss of function mutations in this gene leads to duce the responsiveness of MC3R and MC4R to the onset of obesity. Obesity linked to mutations α- and β-MSH. On the other hand, single-minded in LEP has a prevalence of < 1/1,000,000 and 1 (SIM1) acts as a facilitator of MC4R activi- autosomal recessive inheritance. LEP was first ty. MC4R activity also stimulates the release of linked to human Mendelian obesity in 1997 by brain-derived neurotrophic factor (BDNF), which Montague
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