Extended Data Figure 2. FGF-21 promotes renal gluconeogenesis via Adrb2-dependent neural hardwiring.
Consistent with previous reports, we find that chronic FGF-21 infusion increases energy expenditure and improves metabolic health in diet-induced obese mice. (A)-(G) Body weight, activity, energy expenditure, food and water intake during the first week of FGF-21 or vehicle infusion. Throughout this figure, unless otherwise specified, groups were compared by the 2-tailed unpaired Student’s t-test. In panels (A)-(L), n=5 per group. (H)-(L) Body weight and fat, tissue triglyceride content, blood glucose, and plasma insulin concentrations in week 4 of FGF-21 infusion. (M) Jugular vein plasma FGF-21 concentrations in rats infused with FGF-21 into the third ventricle (ICV) (n=4 vehicle-treated and 5 FGF-21-treated rats in panels (M)-(O)). (N)-(O) Blood glucose and plasma insulin. (P)-(R) Plasma FGF-21, blood glucose, and plasma insulin concentrations in WT and Klbf/f;Camk2a-Cre mice (n=6 per group). (S)-(U) Plasma FGF-21, blood glucose, and plasma insulin concentrations in FGF-21 infused mice, chemically sympathectomized with 6-OHDA (n=4 per group). In panels (S)-(FF), groups were compared by ANOVA with Tukey’s multiple comparisons test. (V)-(W) Hepatic and renal glucose production (n=4 per group). (X)-(Z) Plasma FGF-21, blood glucose, and plasma insulin concentrations in mice infused with FGF-21 and treated with the nonselective Adrb antagonist propranolol (n=5 per group). (AA)-(BB) Hepatic and renal glucose production (n=5 per group). (CC) Validation of Adrb1 and Adrb2 antagonists: epinephrine-stimulated renal glucose production (n=5 per group). For clarity of presentation, statistical comparisons were not performed. (DD) Plasma FGF-21 concentrations in FGF-21 infused mice treated with antagonists of Adrb1 (betaxolol) or Adrb2 (butoxamine) (in panels (DD)-(FF), n=6 [vehicle and Adrb2 antagonist-treated] or 5 per group [Adrb1 antagonist-treated]). (EE) Blood glucose. (FF) Plasma insulin concentrations. (GG) Plasma FGF-21 concentrations in vehicle- and FGF-21-infused WT and whole-body Adrb2 KO littermates (in panels (GG)-(II), n=4 (vehicle-treated) or 5 (FGF-21-treated) per group. (HH)-(II) Blood glucose and plasma insulin concentrations. (JJ) Plasma corticosterone in sham-operated and adrenalectomized mice. ADX mice were implanted with a subcutaneous pump to deliver corticosterone to match concentrations in 24 hr fasted mice, in order to avoid corticosterone as a potential phenotypic confounder. (KK) Plasma FGF-21. (LL)-(MM) Hepatic and renal glucose production. (NN)-(OO) Blood glucose and plasma insulin concentrations. In panels (JJ)-(OO), n=5 per group, and fed vs. 24 hr fasted and sham vs. ADX mice were compared by the 2-tailed unpaired Student’s t-test. In all panels, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.