As both P2X4 and P2X7 are highly upregulated in murine adipose tissues in response to high fat diet feeding (Tian et al, 2020) and thermoneutrality as shown in the current study, we demonstrated that combined P2X4 and P2X7 inhibition on myeloid cells protects against obesity-associated metabolic derangements such as insulin resistance, impaired glucose tolerance and dyslipidemia. Here, P2RX4 is linked to obesity due to melanocortin 4 receptor deficiency.