Obesity genetics in mouse and human: back and forth, and back again

Abstract

Obesity is a major public health concern. This condition results from a constant and complex interplay between predisposing genes and environmental stimuli. Current attempts to manage obesity have been moderately effective and a better understanding of the etiology of obesity is required for the development of more successful and personalized prevention and treatment options. To that effect, mouse models have been an essential tool in expanding our understanding of obesity, due to the availability of their complete genome sequence, genetically identified and defined strains, various tools for genetic manipulation and the accessibility of target tissues for obesity that are not easily attainable from humans. Our knowledge of monogenic obesity in humans greatly benefited from the mouse obesity genetics field. Genes underlying highly penetrant forms of monogenic obesity are part of the leptin-melanocortin pathway in the hypothalamus. Recently, hypothesis-generating genome-wide association studies for polygenic obesity traits in humans have led to the identification of 119 common gene variants with modest effect, most of them having an unknown function. These discoveries have led to novel animal models and have illuminated new biologic pathways. Integrated mouse-human genetic approaches have firmly established new obesity candidate genes. Innovative strategies recently developed by scientists are described in this review to accelerate the identification of causal genes and deepen our understanding of obesity etiology. An exhaustive dissection of the molecular roots of obesity may ultimately help to tackle the growing obesity epidemic worldwide.

Keywords: Genetics; Genome-wide association study; Human; Integrative biology; Knock-out; Monogenic obesity; Mouse; Next generation sequencing; Polygenic obesity; Transgenic.

Figure 1. Genes involved in the leptin-melanocortin pathway that have been associated with monogenic obesity through their influence on food intake and energy expenditure.

Leptin secreted from adipose tissue binds to the leptin receptor in the hypothalamus. Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production, which undergoes post-translational modifications to produce peptides such alpha and beta-melanocyte-stimulating hormone (α and βMSH) via the processing of prohormone convertase 1(PC1/3) and carboxypeptidase E (CPE) enzymes. Alpha and βMSH bind to melanocortin 3 and melanocortin 4 receptors (MC3R and MC4R) and induce their activity. Melanocortin 2 receptor accessory protein 2 (MRAP2) can reduce the responsiveness of both MC3R and MC4R to α and βMSH and result in obesity. On the other hand, Single-minded 1 (SIM1) acts as a facilitator of MC4R activity. Increase in the MC3R and MC4R activities result in a decrease in food intake and increase in energy expenditure. MC4R activity also stimulates release of Brain-derived neurotrophic factor (BDNF) which will bind to the neurotrophin receptor (TrkB) and influence food intake and energy expenditure. Aside from activation of the POMC, leptin binding to its receptor also activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. This pathway, through the help of Src homology 2 B adapter protein 1 (SH2B1), results in activation of Signal transducer and activator of transcription 3 (STAT3). STAT3 will then migrate to the nucleus with the help of Tubby bipartite transcription factor (TUB) and activate its target genes related to energy homeostasis and mediate in the anorexigenic effects of leptin.

Figure 2. Processing of the POMC precursor protein.

Adrenocorticotropic hormone (ACTH) and β-lipotropin are products generated in the corticotrophic cells of the anterior pituitary under the control of corticotropin releasing hormone (CRH). Alpha-melanocyte stimulating hormone (α-MSH), corticotropin-like intermediate lobe peptide (CLIP), γ-lipotropin and β-endorphin are products generated in the intermediate lobe of the pituitary under the control of dopamine. α-, β- and γ-MSH are collectively referred to as melanotropin or intermedin.

Figure 3. General overview of mutagenesis and inbreeding in mice.

Congenic, recombinant inbred and consomic mice are obtained when part of the genome of one mouse strain is transferred to another strain by backcrossing the donor mouse to the receiver strain. In congenic mouse, the offspring resembles the parent strain except for the mutated chromosomal segment, whereas in consomic strain, the offspring carries an entire chromosome from the donor strain. Recombinant inbred strains are obtained by cross breeding of inbred mice to increase their genotypic diversity and carrying a series of brother-sister mating for multiple generations.

Figure 4. Graphical representation of the main concepts of the review.

Summary of the major concepts in methodology of mouse include natural, chemical and insertional mutagenesis, as well as inbreeding and genetic manipulation techniques. In humans, linkage analysis, homozygous mapping, candidate gene studies, genome-wide association studies (GWAS) and whole exome/genome studies (WES/WGS) are discussed. These methodologies have led to genetic studies in monogenic and polygenic obesity, where mouse models paved the way for genetic discoveries in humans. The reverse concept also holds true, as genetic discoveries in humans led to development of new mouse models. In recent attempts of genetic discovery, an integrative approach of animal and human studies have promoted new gene discoveries as well as functional analysis. Current studies are utilizing innovative approaches such as use of omics, hypothesis driven GWAS, expression studies, improved genetic manipulation techniques, gene × gene or gene x environment analysis as well as evolutionary analysis to improve our understanding of the genetic architecture of obesity.