FIG. 8.

Mechanism for FBPase increasing liver FAO and regulating food intake. A: Liver OGT mRNA and OGT Western blot protein levels in transgenic (TG) and negative (NEG) littermate mice using RL2 antibody (n = 4). *P < 0.05 vs. NEG. Liver PGC1-α mRNA levels (B) and PPARα mRNA levels (C) as measured by real-time PCR (n = 4). *P < 0.05 vs. NEG, one-way ANOVA. All data expressed as mean ± SEM. D: Schematic of mechanism by which FBPase increases FAO in the liver. We propose that elevated F6P increases flux through the HBP (as evidenced by an increase in OGT levels), triggering an upregulation of the FAO regulator, PGC1-α that in turn activates PPARα to activate the rate-limiting enzyme in liver FAO, CPT1-a. E: Schematic of mechanism for the overall action of liver FBPase as a regulator of appetite and adiposity. We propose that liver FBPase is upregulated by obesity and/or fat in the diet. This increase in FBPase in the liver appears to be triggering an increase in FAO from the liver, as indicated by a higher concentration of circulating BHB in the TG mice compared with the NEG littermates. BHB then stimulates CCK secretion (which may act synergistically with leptin), which acts on the CCK1R on the vagus nerve to send a signal to the brain to inhibit the appetite stimulating neuropeptides, AgRP and NPY, and in turn reduce food intake and body weight. The bold arrows indicate the proposed mechanism, and the dotted arrows show direct effects. (A high-quality color representation of this figure is available in the online issue.)