eCB pathways involved in obesity-/HFD-associated CKD eCB pathways involved in obesity-/HFD-associated CKD. Obesity/HFD upregulates the eCB tone via CB1R and CB2R found in the brain/central nervous system (CNS), peripheral tissues, and various cells of the kidneys. eCB pathways involved in obesity-/HFD-associated CKD. Obesity/HFD upregulates the eCB tone via CB1R and CB2R found in the brain/central nervous system (CNS), peripheral tissues, and various cells of the kidneys. In the renal PTCs, obesity-induced lipotoxicity is modulated by the CB1R-coupled α-subunit of heterotrimeric Gi/o protein (Gαi/o)-protein kinase A (PKA) axis, which mediates the downstream activation of the liver kinase B1 (LKB1)/AMPK/ACC signaling pathway; this decreases fatty acid β-oxidation and increases inflammation and fibrosis, resulting in CKD. The CB1R in the peripheral tissues increases hepatic de novo fatty acid synthesis and obesity-induced metabolic and hormonal abnormalities, whereas the CB1R in the brain increases appetite, leptin, obesity, and insulin resistance, which contribute to the development of CKD. Although the CB2R is found in all of these tissues, its role is still unclear. The pathway discussed by Udi et al.8 in this issue of the Journal of the American Society of Nephrology has been highlighted in yellow. ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; eCB, endocannabinoid. Peter F. Mount, and Luis A. Juncos JASN 2017;28:3429-3432 ©2017 by American Society of Nephrology