Highlights d Hypothalamic tanycytes synthesize and secrete Fgf21 under nutritional stress d Palmitate oxidation in tanycytes triggers Fgf21 expression via the ROS/p38-MAPK pathway d Deletion of tanycytic Fgf21 reduces fat depot size and promotes energy expenditure d Deletion of tanycytic Fgf21 promotes lipolysis and browning of WAT

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IntroductionSeveral data suggest that excitotoxicity due to excessive glutamatergic neurotransmission may be an important factor in the mechanisms of motor neuron (MN) death occurring in amyotrophic lateral sclerosis (ALS). We have previously shown that the overactivation of the Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamate receptor type, through the continuous infusion of AMPA in the lumbar spinal cord of adult rats during several days, results in progressive rear limb paralysis and bilateral MN degeneration. Because it has been shown that energy failure and oxidative stress are involved in MN degeneration, in both ALS and experimental models of spinal MN degeneration, including excitotoxicity, in this work we tested the protective effect of the energy substrates pyruvate and β-hydroxybutyrate (βHB) and the antioxidants glutathione ethyl ester (GEE) and ascorbate in this chronic AMPA-induced neurodegeneration.ResultsAMPA infusion induced remarkable progressive motor deficits, assessed by two motor tasks, that by day seven reach bilateral rear limb paralysis. These effects correlate with the death of >80% of lumbar spinal MNs in the infused and the neighbor spinal cord segments, as well as with notable astrogliosis in the ventral horns, detected by glial fibrillary acidic protein immunohistochemistry. Co-infusion with pyruvate or βHB notably prevented the motor deficits and paralysis, decreased MN loss to <25% and completely prevented the induction of astrogliosis. In contrast, the antioxidants tested were ineffective regarding all parameters analyzed.ConclusionsChronic progressive excitotoxicity due to AMPA receptors overactivation results in MN death and astrogliosis, with consequent motor deficits and paralysis. Because of the notable protection against these effects exerted by pyruvate and βHB, which are well established mitochondrial energy substrates, we conclude that deficits in mitochondrial energy metabolism are an important factor in the mechanisms of this slowly developed excitotoxic MN death, while the lack of protective effect of the antioxidants indicates that oxidative stress seems to be less significant factor. Because excitotoxicity may be involved in MN degeneration in ALS, these findings suggest possible preventive or therapeutic strategies for the disease.

Daily recurring events can be predicted by animals based on their internal circadian timing system. However, independently from the suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system in mammals, restriction of food access to a particular time of day elicits food anticipatory activity (FAA). This suggests an involvement of other central and/or peripheral clocks as well as metabolic signals in this behavior. One of the metabolic signals that is important for FAA under combined caloric and temporal food restriction is β-hydroxybutyrate (βOHB). Here we show that the monocarboxylate transporter 1 (Mct1), which transports ketone bodies such as βOHB across membranes of various cell types, is involved in FAA. In particular, we show that lack of the Mct1 gene in the liver, but not in neuronal or glial cells, reduces FAA in mice. This is associated with a reduction of βOHB levels in the blood. Our observations suggest an important role of ketone bodies and its transporter Mct1 in FAA under caloric and temporal food restriction.