Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans

Abstract

Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating/drinking behavior via FGF receptor 1/Klothoβ (FGFR1/KLB) complexes expressed in adipocytes, pancreatic acinar cells, and the nervous system in mice. Chronic administration of recombinant FGF21 or engineered variants improves metabolic health in rodents, nonhuman primates, and humans; however, the rapid turnover of these molecules limits therapeutic utility. Here we show that the bispecific anti-FGFR1/KLB agonist antibody BFKB8488A induced marked weight loss in obese cynomolgus monkeys while elevating serum adiponectin and the adipose expression of FGFR1 target genes, demonstrating its action as an FGF21 mimetic. In a randomized, placebo-controlled, single ascending-dose study in overweight/obese human participants, subcutaneous BFKB8488A injection caused transient body weight reduction, sustained improvement in cardiometabolic parameters, and a trend toward reduction in preference for sweet taste and carbohydrate intake. These data suggest that specific activation of the FGFR1/KLB complex in humans can be used as therapy for obesity-related metabolic defects.

FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution

“…A potential limitation of this approach, however, is that the macronutrients are presented in an arguably unnatural fashion (i.e., as liquids). Consistent with our data, though, administration of an FGF21 analog to obese subjects decreased preference for sweet tasting food and carbohydrate intake 41 . Moreover, the physiological relevance of FGF21 in regulating carbohydrate intake is demonstrated by single nucleotide polymorphisms (SNPs) at the FGF21 locus associating with increased intake of sweets 42 and carbohydrates 43,44 .…”

The Effect of FGF21 and Its Genetic Variants on Food and Drug Cravings, Adipokines and Metabolic Traits

“…Additionally it improved fasting insulin (FI) and adiponectin levels [ 27 , 28 , 29 ]. Subcutaneous administration of a FGF21/β-klotho complex reduced body weight and the cardio-metabolic risk in humans while data also suggest effects on sweet preference and the consumption of carbohydrate rich foods [ 30 ].…”

Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules 

“…KCNE2 [115], DLL1 [116], ACVR1C [117], RGS3 [118], MLXIPL (MLX interacting protein like) [119], PAG1 [120], SLC2A10 [121] and GRB14 [122] play important role in type 2 diabetes mellitus progression. A recent investigation has indicated that GPIHBP1 [123], FGFRL1 [124], DAPK2 [125], MAP3K5 [126], ANKK1 [127], GK (glycerol kinase) [128], SPHK1 [129], GNG3 [130], FSTL3 [131], SLIT2 [132], CCDC80 [133], RND3 [134], PTGER4 [135], RUNX1 [136], ADAM12 [137], OLR1 [138], THBS1 [139], CD28 [140], TRPV4 [141], ATRN (attractin) [142], MRC1 [143], SEMA3C [144], HTR2B [145], NOX4 [146], TACR1 [147], BAMBI [148], PDGFD (platelet derived growth factor D) [149], APLN (apelin) [150], MFAP5 [151] and LUM (lumican) [152] are associated with a development of obesity. A previous investigation found that DDR1 [153], TAB1 [154], NEK8 [155], SERPINE2 [156], FCGR2B [157], ANGPT2…”