Fibroblast growth factor 21 (FGF21) is a hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism, and repress growth1; however the site of action of these diverse effects remains unclear. FGF21 signals through a heteromeric cell surface receptor composed of one of three FGF receptors (FGFR1c, 2c, or 3c) in complex with β-Klotho2-4, a single-pass transmembrane protein that is enriched in metabolic tissues5. Here we show that in addition to its known effects on peripheral metabolism, FGF21 increases systemic glucocorticoid levels, suppresses physical activity, and alters circadian behavior, all features of the adaptive starvation response. These effects are mediated through β-Klotho expression in the suprachiasmatic nucleus (SCN) of the hypothalamus and the dorsal vagal complex (DVC) of the hindbrain. Mice lacking the β-Klotho gene (Klb) in these regions are refractory to these effects, as well as those on metabolism, insulin, and growth. These findings demonstrate a crucial role for the nervous system in mediating the diverse physiologic and pharmacologic actions of FGF21.

SUMMARY Caloric restriction (CR) extends lifespan in mammals, yet the mechanisms underlying its beneficial effects remain unknown. The manner in which CR has been implemented in longevity experiments is variable, with both timing and frequency of meals constrained by work schedules. It is commonplace to find that nocturnal rodents are fed during the daytime, and meals are spaced out, introducing prolonged fasting intervals. Since implementation of feeding paradigms over the lifetime is logistically difficult, automation is critical, but existing systems are expensive and not amenable to scale. We have developed a system that controls duration, amount and timing of food availability, and records feeding and voluntary wheel-running activity in mice. Using this system, mice were exposed to temporal or caloric restriction protocols. Mice under CR self-imposed a temporal component by consolidating food intake and unexpectedly increasing wheel-running activity during the rest phase, revealing previously unrecognized relationships among feeding, metabolism and behavior.

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The circadian systems of rodents respond to light pulses presented during the subjective night with phase shifts and altered cellular activity in the suprachiasmatic nuclei (SCN), including expression of immediate-early genes (IEGs) such as c-fos. A recent study showed that a nonphotic stimulus (an air disturbance generated by a fan) that does not normally induce the expression of c-fos-like immunoreactivity in the SCN of rats can be made to do so after being paired repeatedly with a light pulse in a Pavlovian conditioning paradigm. Furthermore, after conditioning (but not after noncontingent exposure to these stimuli), the fan also induced phase shifts in activity and body temperature rhythms comparable to those produced by light. The authors performed three experiments designed to replicate and extend these findings in rats. In experiment 1, rats were tested for conditioning effects of repeated pairings of a light pulse with a neutral air disturbance under a full photoperiod. In experiment 2, a modified conditioning paradigm was used in which a skeleton photoperiod served as both the entraining zeitgeber and the unconditioned stimulus. Animals in the paired and unpaired training conditions were exposed to both the light pulse and the air disturbance, but the air disturbance signaled the onset of light in the paired condition only. Phase shifts of wheel-running activity rhythms and gene expression in the SCN, intergeniculate leaflet, and paraventricular nucleus of the thalamus were assessed in animals following either of the training conditions or the control procedures. Experiment 3 assessed whether the air disturbance could entrain the circadian activity rhythms of rats with or without previous pairing with light in a classical conditioning paradigm. No evidence for classical conditioning, nor for unconditioned effects of the air disturbance on the circadian system, was found in these studies.

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1In a screen of voluntary wheel-running behavior designed to identify genetic mouse 2 models of chronic fatigue in ENU mutagenized C57BL/6J mice, we discovered two lines 3 that showed aberrant wheel-running patterns. These lines both stem from a single 4 original founder identified as a low body-weight candidate in a recessive screen. 5