ABSTRACT: Although regulation of energy metabolism has been linked with multiple disorders, its role in depression and responsiveness to antidepressants is less-known. We found that an epigenetic and energetic agent, acetyl-L-carnitine (LAC, oral administration), rapidly rescued the depressive- and central and systemic metabolic-like phenotype of LAC-deficient Flinders Sensitive Line (FSL) rats. After acute stress during LAC treatment, a subset of FSL continued to respond to LAC (rFSL), whereas the other subset did not respond (nrFSL). RNAseq for the ventral dentate-gyrus (vDG), a mood-regulatory region, identified metabolic factors as key markers predisposing to depression (insulin receptors Insr, glucose transporters Glut-4 and Glut-12, the regulator of appetite Cartpt) and to LAC responsiveness (leptin receptors Lepr, metabotropic glutamate receptors-2 mGlu2, neuropeptide-Y NPY, and mineralocorticoid receptors MR). Furthermore, we found that stress-induced treatment-resistance in nrFSL shows a new gene profile, including the metabolic regulator factors Elovl7 and Cyb5r2 and the synaptic regulator NPAS4. Finally, while improving central energy regulation and exerting rapid antidepressant-like effects, LAC corrected a systemic hyperinsulinemia and hyperglycemia.tance in rFSL and failed to do that in nrFSL. These findings establish CNS energy regulation as factor to be considered for the development of better therapeutics. Agents, like LAC, which regulate metabolic factors and reduce glutamate overflow, could rapidly ameliorate depression and could also be considered for treatment of insulin-resistance in depressed subjects. The approach here serves as a model for identifying markers and underlying mechanisms of predisposition to diseases and treatment responsiveness that may be useful in translation to human behavior and psychopathology. Ventral dentate gyrus RNA from 3 biological replicates per group (vehicle-FRL, vehicle-FSL, LAC-treated not-responder FSL, LAC-treated responder FSL, all males) was used for library prep (TruSeq Stranded Total RNA with Ribo-Zero Human/Mouse/Rat) and sequenced on Illumina HiSeq2500 at the Genomic Core facility at The Rockefeller University. Each sample was provided with a unique adapter and all samples were put in the same pool and run in multiple lanes to control for lane effects with a sequencing depth of about 30M (100bp, single).
