The promise of new anti-obesity therapies arising from knowledge of genetic obesity traits

Abstract

Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the interaction between genetic predisposition and environmental factors. Polygenic variants are frequent and confer small effect sizes. Rare monogenic obesity syndromes are caused by defined pathogenic variants in single genes with large effect sizes. Most of these genes are involved in the central nervous regulation of body weight; for example, genes of the leptin-melanocortin pathway. Clinically, patients with monogenic obesity present with impaired satiety, hyperphagia and pronounced food-seeking behaviour in early childhood, which leads to severe early-onset obesity. With the advent of novel pharmacological treatment options emerging for monogenic obesity syndromes that target the central melanocortin pathway, genetic testing is recommended for patients with rapid weight gain in infancy and additional clinical suggestive features. Likewise, patients with obesity associated with hypothalamic damage or other forms of syndromic obesity involving energy regulatory circuits could benefit from these novel pharmacological treatment options. Early identification of patients affected by syndromic obesity will lead to appropriate treatment, thereby preventing the development of obesity sequelae, avoiding failure of conservative treatment approaches and alleviating stigmatization of patients and their families.

Fig. 1. Central nervous system regulation of body weight via the leptin–melanocortin pathway.

Leptin is produced and secreted from adipocytes in proportion to the amount of adipose tissue mass and exerts its function as a satiety factor in the hypothalamic arcuate nucleus. It binds to the leptin receptor (LepR) present on specific neuron populations: neuropeptide Y (NPY)–agouti-related protein (AgRP) neurons and pro-opiomelanocortin (POMC) neurons. The Src-homology-2B adaptor protein 1 (SH2B1) is a crucial molecule in leptin-mediated signal transduction. In NPY–AgRP neurons, leptin downregulates the expression of the orexigenic AgRP, which acts as an inverse agonist at the melanocortin 4 receptor (MC4R). In POMC neurons, leptin induces the expression of POMC. Proprotein convertase subtilisin/kexin-type 1 (PCSK1) and carboxypeptidase (CPE) catalyse the processing of peptide hormones including α-melanocyte stimulating hormone (MSH), which serves as an anorexigenic agonist at the MC4R. Pleckstrin homology domain interacting protein (PHIP) serves as an enhancer of POMC transcription. Nuclear receptor coactivator 1 (NCOA1) modulates the function of nuclear hormone receptors and transcription factors by enhancing or suppressing the expression of target genes. Brain-derived neurotrophic factor (BDNF), via its receptor neurotrophic receptor tyrosine kinase 2 (NTRK2), modulates leptin-mediated synaptic plasticity of neurons. α-MSH binds to and actives MC4R present on neurons in the paraventricular nucleus, which controls appetite and links the energy state of long-term adipose stores to feeding behaviour. Melanocortin receptor accessory protein 2 (MRAP2) is an accessory protein of melanocortin receptors and regulates their function. Single-minded homologue 1 (SIM1) is a basic helix–loop–helix transcription factor and is required for the development of neurons of the paraventricular nucleus. An agonist at the MC4R (setmelanotide) is useful for treating monogenic forms of obesity affecting genes upstream of the MC4R and certain genetic variants of the MC4R.