Are adipocytes via the FGFR1-KLB partnership the primary or even specific target of systemic or local FGF21 signal observed in diverse body tissues? FGF21-stimulated changes in systemic metabolites and adipokines whose receptors are distributed widely have potential to indirectly affect practically all body tissues. Moreover, adipocytes that are characterized by expression of FGFR1-KLB and present in the microenvironment of most, if not all, tissues have potential to affect functions of adjacent tissues via FGF21-controlled paracrine products in the microenvironment. A careful dissection of both FGFR isotypes and KLB and signals elicited by the partnership in parenchymal and adipocytes of diverse organs that show a response to systemic FGF21 is required to clarify whether non-adipocyte cells constitute additional direct targets for FGF21. It has been suggested that FGF21 may signal directly in hepatocytes (54), pancreatic islet beta cells (31, 32), and cells in the suprachiasmatic nucleus of the hypothalamus and the dorsal vagal complex of the hindbrain (55, 56).
