Abstract
Daily feeding schedules generate food anticipatory rhythms of behavior and physiology that exhibit canonical properties of circadian clock control. The molecular mechanisms and location of food-entrainable circadian oscillators hypothesized to control food anticipatory rhythms are unknown. In 2008, Fuller et al reported that food-entrainable circadian rhythms are absent in mice bearing a null mutation of the circadian clock gene Bmal1 and that these rhythms can be rescued by virally-mediated restoration of Bmal1 expression in the dorsomedial nucleus of the hypothalamus (DMH) but not in the suprachiasmatic nucleus (site of the master light-entrainable circadian pacemaker). These results, taken together with controversial DMH lesion results published by the same laboratory, appear to establish the DMH as the site of a Bmal1-dependent circadian mechanism necessary and sufficient for food anticipatory rhythms. However, careful examination of the manuscript reveals numerous weaknesses in the evidence as presented. These problems are grouped as follows and elaborated in detail: 1. data management issues (apparent misalignments of plotted data), 2. failure of evidence to support the major conclusions, and 3. missing data and methodological details. The Fuller et al results are therefore considered inconclusive, and fail to clarify the role of either the DMH or Bmal1 in the expression of food-entrainable circadian rhythms in rodents.
Highlights
Journal of Circadian Rhythms 2009, 7:3 http://www.jcircadianrhythms.com/content/7/1/3 to daily feeding schedules [3,4,5]
Efforts to localize food-entrainable circadian oscillators for behavior began over 30 years ago, but until the turn of the 21st century were limited to a few laboratories, and yielded primarily negative findings
Gooley et al [11] reported that ablation of ~70–90% of the dorsomedial hypothalamus (DMH), by localized injection of the neurotoxin ibotenic acid, severely attenuated or eliminated food anticipatory rhythms of activity, sleep-wake and temperature rhythms in rats
Summary
In this review of Fuller et al [12,30] we have identified a large number of flaws in the evidence supporting the claim that a Bmal1-dependent circadian mechanism in the DMH is sufficient to drive food-entrainable rhythms of activity and body temperature in mice. While numerous, these flaws are by no means minor. The evidence as presented in Fuller et al [12] clearly does not meet the necessary standards
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