Thus, the present study demonstrated a novel molecular basis for Jak3 in the gut–brain communication and its physiological and pathophysiological implications in CLGI, obesity-associated glycemic dysregulation, gut dysbiosis and the associated cognitive impairment, which, in future, would have a wider impact on our understanding of the gut–microbiome–brain interactions and dementia. Here, JAK3 is linked to obesity due to melanocortin 4 receptor deficiency.