Whilst several hypothalamic-acting, blood-borne hormones – including the active thyroid hormone (T3), oestrogen and glucagon-like peptide-1 (GLP-1) – have been reported to regulate obesity (Larabee et al. 2020), here we will focus on the dysregulation of leptin signalling within the hypothalamus. This evidence concerns the gene GCG and obesity due to melanocortin 4 receptor deficiency.