-
Molecules and Cells Apr 2022A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular... (Review)
Review
A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular signaling. An interesting linkage between cilia and obesity has been revealed by studies of the human genetic ciliopathies Bardet-Biedl syndrome and Alström syndrome, in which obesity is a principal manifestation. Mouse models of cell type-specific cilia dysgenesis have subsequently demonstrated that ciliary defects restricted to specific hypothalamic neurons are sufficient to induce obesity and hyperphagia. A potential mechanism underlying hypothalamic neuron cilia-related obesity is impaired ciliary localization of G protein-coupled receptors involved in the regulation of appetite and energy metabolism. A well-studied example of this is melanocortin 4 receptor (MC4R), mutations in which are the most common cause of human monogenic obesity. In the paraventricular hypothalamus neurons, a blockade of ciliary trafficking of MC4R as well as its downstream ciliary signaling leads to hyperphagia and weight gain. Another potential mechanism is reduced leptin signaling in hypothalamic neurons with defective cilia. Leptin receptors traffic to the periciliary area upon leptin stimulation. Moreover, defects in cilia formation hamper leptin signaling and actions in both developing and differentiated hypothalamic neurons. The list of obesity-linked ciliary proteins is expending and this supports a tight association between cilia and obesity. This article provides a brief review on the mechanism of how ciliary defects in hypothalamic neurons facilitate obesity.
Topics: Animals; Cilia; Humans; Hyperphagia; Hypothalamus; Leptin; Mice; Obesity
PubMed: 35387896
DOI: 10.14348/molcells.2022.2046 -
Advanced Biology Aug 2023Nonsyndromic monogenic obesity (NSMO) is a class of individual obesity that is independent of the environment and caused by a single gene mutation. It is mostly caused...
Nonsyndromic monogenic obesity (NSMO) is a class of individual obesity that is independent of the environment and caused by a single gene mutation. It is mostly caused by mutations in LEP, LEPR, PCSK1, as well as some rare mutations in UCP3, NR0B2, and PPARG. Among 30 obesity patients, five patients are identified with positive gene detection. For the first time, the c.624C>T mutation associated with PCSK1, and the c.50G>A and c.293_301delinsAC mutations associated with NR0B2, as well as the obesity phenotype mutation (c.284A>G) associated with PPARG is confirmed. Following this, the genotype-clinical phenotype, mutation hotspots, and mutation distributions of each gene are summarized, and the genetic characteristics of NSMO are analyzed. The locations of mutation c.50G>A, and c.284A>G are highly conserved according to the sequencing alignment. According to the findings, the c.624C>T mutation in PCSK1 is a newly discovered synonymous mutation, but it can result in significant early-onset obesity. Additionally, the mutation of c.284A>G(PPARG) can lead to a variety of clinical phenotypes and the mutation of UCP3 and NR0B2 may increase the risk of type 2 diabetes mellitus. This study enriches the human NSMO gene mutation database and provides a scientific basis for clinically accurate diagnosis and treatment.
Topics: Humans; Diabetes Mellitus, Type 2; PPAR gamma; Obesity; Mutation; Phenotype
PubMed: 37083215
DOI: 10.1002/adbi.202300061 -
Journal of Clinical Medicine Feb 2024Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can... (Review)
Review
Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can achieve limited weight loss. Bariatric surgery is an effective way of achieving substantial weight loss as well as glycemic control secondary to weight-related type 2 diabetes mellitus. It has been suggested that an anorexigenic gut hormone response following bariatric surgery contributes to weight loss. Understanding the changes in gut hormones and their contribution to weight loss physiology can lead to new therapeutic treatments for weight loss. Two distinct types of neurons in the arcuate hypothalamic nuclei control food intake: proopiomelanocortin neurons activated by the anorexigenic (satiety) hormones and neurons activated by the orexigenic peptides that release neuropeptide Y and agouti-related peptide (hunger centre). The arcuate nucleus of the hypothalamus integrates hormonal inputs from the gut and adipose tissue (the anorexigenic hormones cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin, and others) and orexigeneic peptides (ghrelin). Replicating the endocrine response to bariatric surgery through pharmacological mimicry holds promise for medical treatment. Obesity has genetic and environmental factors. New advances in genetic testing have identified both monogenic and polygenic obesity-related genes. Understanding the function of genes contributing to obesity will increase insights into the biology of obesity. This review includes the physiology of appetite control, the influence of genetics on obesity, and the changes that occur following bariatric surgery. This has the potential to lead to the development of more subtle, individualised, treatments for obesity.
PubMed: 38546831
DOI: 10.3390/jcm13051347 -
Current Diabetes Reports Jul 2020The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective... (Review)
Review
PURPOSE OF REVIEW
The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity.
RECENT FINDINGS
In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and developmental disorders might have poorer outcomes. There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients.
Topics: Bariatric Surgery; Humans; Mass Screening; Obesity, Morbid; Prevalence
PubMed: 32729070
DOI: 10.1007/s11892-020-01327-7 -
Pharmacological Research May 2023The better understanding of the molecular causes of rare genetic obesities and its associated phenotype involving the hypothalamus allows today to consider innovative... (Review)
Review
The better understanding of the molecular causes of rare genetic obesities and its associated phenotype involving the hypothalamus allows today to consider innovative therapeutics focused on hunger control. Several new pharmacological molecules benefit patients with monogenic or syndromic obesity. They are likely to be among the treatment options for these patients in the coming years, helping clinicians and patients prevent rapid weight progression and eventually limit bariatric surgery procedures, which is less effective in these patients. Their positioning in the management of such patients will be needed to be well defined to develop precision medicine in genetic forms of obesity.
Topics: Humans; Obesity; Bariatric Surgery
PubMed: 37037398
DOI: 10.1016/j.phrs.2023.106763 -
Advanced Biology Oct 2022Growing evidence supports syndromic and nonsyndromic causes of obesity, including genome-wide association studies, candidate gene analysis, advanced genetic technology... (Review)
Review
Growing evidence supports syndromic and nonsyndromic causes of obesity, including genome-wide association studies, candidate gene analysis, advanced genetic technology using next-generation sequencing (NGS), and identification of copy number variants. Identification of susceptibility genes impacts mechanistic understanding and informs precision medicine. The cause of obesity is heterogeneous with complex biological processes playing a role by controlling peptides involved in regulating appetite and food intake, cellular energy, and metabolism. Evidence for heritability shows genetic components contributing to 40%-70% of obesity. Monogenic causes and obesity-related syndromes are discussed and illustrated as well as biological pathways, gene interactions, and factors contributing to the obesity phenotype. Over 550 obesity-related single genes have been identified and summarized in tabular form with approximately 20% of these genes have been added to obesity gene panels for testing by commercially available laboratories. Early studies show that about 10% of patients with severe obesity using NGS testing have a pathogenic gene variant. Discussion to help characterize gene-gene interactions and disease mechanisms for early diagnosis, treatment, and risk factors contributing to disease is incorporated in this review.
Topics: Humans; Genome-Wide Association Study; Obesity; Phenotype; DNA Copy Number Variations; High-Throughput Nucleotide Sequencing
PubMed: 35680611
DOI: 10.1002/adbi.202101154 -
Maedica Sep 2022Obesity is defined by an imbalance between energy expenditure and energy consumption. Presently, it is considered a global problem because people are consuming junk food...
Obesity is defined by an imbalance between energy expenditure and energy consumption. Presently, it is considered a global problem because people are consuming junk food and doing less physical activity in every country of the world. It is all due to sedentary life style. The currently available drugs for the treatment of obesity are not giving satisfactory results as they have many adverse effects along with rebound obesity complications. To evaluate new drug in pre-clinical study, we need to have better supportive animal models. Obesity can be induced by giving drugs, fat food, surgical procedures, and by genetic modifications. In the present review, various obesity induced models have been explained to evaluate new compounds. In experimental animal models, monogenic and polygenic obesity models have been reviewed, with a proper pathway to prepare new drugs being given. While in the existing models, genetic obesity models were not explained so far, here genetic engineered transgenic models were described to evaluate new anti-obesity drugs. This short review on chemically and surgically induced obesity models aimed to provide a better understanding of the experimental design of obesity.
PubMed: 36540593
DOI: 10.26574/maedica.2022.17.3.706 -
Cells Apr 2022Obesity, one of the major problems in modern human society, is correlated with various diseases, including type 2 diabetes mellitus (T2DM). In particular,... (Review)
Review
Obesity, one of the major problems in modern human society, is correlated with various diseases, including type 2 diabetes mellitus (T2DM). In particular, epidemiological and experimental evidence indicates that obesity is closely linked to at least 13 different types of cancer. The mechanisms that potentially explain the link between obesity and cancer include hyperactivation of the IGF pathway, metabolic dysregulation, dysfunctional angiogenesis, chronic inflammation, and interaction between pro-inflammatory cytokines, endocrine hormones, and adipokines. However, how the largely uniform morbidity of obesity leads to different types of cancer still needs to be investigated. To study the link between obesity and cancer, researchers have commonly used preclinical animal models, particularly mouse models. These models include monogenic models of obesity (e.g., and mice) and genetically modified mouse models of human cancers (e.g., -driven pancreatic cancer, -mutated colorectal cancer, and Her2/neu-overexpressing breast cancer). The experimental results obtained using these mouse models revealed strong evidence of a link between obesity and cancer and suggested their underlying mechanisms.
Topics: Adipokines; Animals; Breast Neoplasms; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Humans; Mice; Obesity
PubMed: 35563777
DOI: 10.3390/cells11091472