Metabolic dysfunction exacerbates Alzheimer's disease (AD) incidence and progression. Here we report that activation of the AMPK pathway, a common target in the management of diabetes, results in gender-divergent cognitive effects in a murine model of the disease. Specifically, our results show that activation of AMPK increases memory dysfunction in males but is protective in females, suggesting that gender considerations may constitute an important factor in medical intervention of diabetes as well as AD.

Highlights d Loss of hepatic JARID1a disrupts large-scale rhythms in transcription d JARID1a is required for the hepatic transcriptomic food response d Mice that lack liver JARID1a have defects in glucose, lipid, and amino acid metabolism

Circadian rhythms are patterns of behavior, physiology, and metabolism that occur within a period of approximately 24 h. These rhythms are generated endogenously, but synchronize to external cues, thus enabling organisms to beneficially align physiological processes to the inherently dynamic, yet predictable, seasonal changes in the day-night cycle. The cell autonomous circadian oscillator temporally coordinates cellular processes, including metabolism, proliferation, cell signaling, organelle function, proteostasis, and DNA damage repair to sustain cellular homeostasis. It is hypothesized that the circadian oscillators evolved as a "flight from light" mechanism to minimize UV damage to single stranded DNA by restricting DNA replication to the nighttime. Support for this hypothesis is accumulating with the recent observation that the circadian rhythm and cell cycle are intimately coupled to each other, so that specific phases of cell cycle occur at a defined phase of the circadian oscillator at single-cell level [1]. Furthermore, chronic circadian disruption perturbs cellular homeostasis and predisposes to cancer. Conversely, numerous cancer cell lines display severe circadian alterations, which likely contribute to aggressive proliferation of the tumor. Hence, it is becoming increasingly important to understand the relevance of circadian rhythm for optimizing fitness

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A powerful use of gene editing technology is the generation of genetic-null (knockout) mutants of human immortalized cell lines. However, a problem that arises in the process of generating such edited lines is that to ensure edit homogeneity, clonal selection must often be performed and, given the genomic instability of immortalized cell lines and the high division number inherent to the clonal selection process, the resulting clone can exhibit genotypic and phenotypic differences from the parental line. Here, we present a system that allows for the generation of genetic null cell lines with an excisable cassette. This system allows for the generation of suitable controls without the need of further rounds of clonal selection.