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Maternal obesity
Published in Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos, New Technologies and Perinatal Medicine, 2019
Tahir A. Mahmood, Rohan Chodankar
A role for the monogenic origins of obesity was first proposed with studies in murine models, followed by a similar discovery in humans. Experiments with a series of mouse obesity genes, including those that encode leptin, the leptin receptor (LEPR), carboxypeptidase E (responsible for processing prohormone intermediates, such as proinsulin, and the orexigenic protein agouti), allowed for significant improvements in knowledge (18–21). Targeted genetic manipulation has also established the vital regulatory role of molecules such as the melanocortin 4 receptor (MC4R), which is vital in the melanocortin pathway, and the orexigenic protein AGRP (22,23). Monogenic recessive forms of human obesity caused by mutations in the genes that encode leptin, LEPR, prohormone convertase 1 (an endopeptidase that is involved in processing prohormones, including insulin and POMC), and POMC, all of which result in a phenotype of excessive energy intake relative to energy expenditure were subsequently discovered (24–27). More frequent forms of obesity are caused by mutations in the gene that encodes MC4R. MC4R deficiency (autosomal-dominant) represents the most common monogenic obesity disorder that has been identified so far (28).
Pharmacological Treatment of Obesity
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Amie A. Ogunsakin, Ayotunde O. Dokun
This is a fixed-dose combination of naltrexone and bupropion. It was FDA approved in September of 2014 for management of obesity. Naltrexone is an opioid antagonist, and bupropion is an aminoketone antidepressant that inhibits dopamine and norepinephrine re-uptake inhibitors, which stimulates pro-opiomelanocortin (POMC) neurons. The exact mechanism of the naltrexone/bupropion combination leading to weight loss is not fully understood [35]. The combination is theorized to work synergistically in the hypothalamus and the mesolimbic dopamine circuit to promote satiety, reduce food intake, and enhance energy expenditure. POMC cells located in the arcuate nucleus of the hypothalamus produce melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin, an endogenous opioid [36,37]. The alpha-MSH activates the melanocortin-4 receptor (MC4R), leading to decreased food intake, increased energy expenditure, and weight loss [38,39]. Beta-endorphin reduces activity of POMC cells by binding to the inhibitory mu-opioid receptor (MOP-R) [40]. Bupropion, a weak dopamine and norepinephrine reuptake inhibitor, enhances POMC cell production and release of alpha-MSH and beta-endorphin [41]. Naltrexone, an opioid antagonist, blocks the MOP-R; therefore, it disrupts beta-endorphin inhibitory feedback on POMC cells [41] (Figure 7.1).
The Genetic Alibi
Published in Roy J. Shephard, Obesity: A Kinesiologist’s Perspective, 2018
The role of many genes in modifying energy balance seems to be mediated through the leptin–melanocortin pathway [16, 36], with actions on the leptin, leptin receptor, pro-opiomelanocortin (POMC), and melanocortin 4 receptor MC4R genes [11, 42]. One report now claims to have identified 32 loci known to be associated with obesity, and 97 loci that could possibly impinge upon obesity [41].
A narrative review of anti-obesity medications for obese patients with osteoarthritis
Published in Expert Opinion on Pharmacotherapy, 2022
Win Min Oo, Ali Mobasheri, David J Hunter
Setmelanotide is an agonist of melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, which regulates energy balance and body weight [128]. Mutations in the MC4R gene result in hyperphagia and severe childhood-onset obesity (0.5% to 5.8% of childhood-onset obesity) [129]. It is approved for treating childhood obesity arising from pro-opiomelanocortin (POMC) [80% (n = 10) achieved ≥10% weight loss at 1 year [130]], proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency [45% (n = 11) achieved ≥10% weight loss at one year [130]] in a personalized medicine approach. In a phase-3 trial, 34.5% (n = 31) achieved a ≥ 10% weight loss in patients with Bardet–Biedl or Alström syndrome [131]. It is administered once daily by the subcutaneous route, using a titration schedule up to a maximum of 3 mg daily [132].
Pharmacoperone drugs: targeting misfolded proteins causing lysosomal storage-, ion channels-, and G protein-coupled receptors-associated conformational disorders
Published in Expert Review of Clinical Pharmacology, 2018
Zhi-Shuai Hou, Alfredo Ulloa-Aguirre, Ya-Xiong Tao
Ideally, antagonist/inhibitor PCs should aid the misfolded mutant to stabilize its native conformation and promote correct trafficking to its site of function (e.g. cell surface PM receptors). Thereafter, antagonist/inhibitor PCs should be easily removed and the rescued protein should exhibit similar specificity and affinity as its WT counterpart, so that the endogenous ligand may bind and activate the rescued protein [6]. A trade-off between affinity and efficiency may exist when antagonists/inhibitors PCs are applied in vivo. Generally, high-affinity antagonist/inhibitor PCs are difficult to dissociate, whereas low-affinity antagonist/inhibitor PCs, although dissociate easier from the rescued receptor, usually require higher effective concentrations that may not be practical for clinical applications. For example, ML00253764 (Ki, 0.17 μM) can rescue melanocortin-4 receptor (MC4R) mutants but with an EC50 of ~10 μM. Ipsen 5i (Ki, 2.0 nM) and Ipsen 17 (Ki, 0.96 nM), which have relatively fast dissociation rates, can rescue MC4R mutants with a EC50 ~ 1000x lower, allowing binding of endogenous ligands [70]. Thus, antagonist/inhibitor PCs should ideally provide the most effective rescue response at the lowest concentration, without losing its ability to easily dissociate from the rescued receptor to facilitate binding of the endogenous ligand [71].
Comparison of weight loss and adverse events of obesity drugs in children and adolescents: a systematic review and meta-analysis
Published in Expert Review of Clinical Pharmacology, 2022
Guangming Zhao, Qi Zhang, Fan Wu, Shuang Yin, Yiqi Xie, Hongyan Liu
Melanocortin-4 receptor mutations is a kind of obesity caused by genetic mutation, which causes hyperphagia, accelerated linear growth and disproportionate hyperinsulinemia. Roux-en-Y gaseous bypass (RYGB) surgery has been used before and achieved good results [44]. Some studies have identified that liraglutide can inhibit excess appetite in patients with melanocortin-4 receptor mutations, improve insulin levels, and eventually make patients lose weight. Although the patients in this study were mainly adults and young people, it could provide ideas for the future treatment of childhood obesity in melanocortin-4 receptor mutations [45].