Distinct transcriptomic effects of intermittent and chronic caloric restriction in mammary fat pad of a breast cancer mouse model

Age-related dysfunction in neuroendocrine signaling, which influences adipose tissue homeostasis, has been implicated in numerous diseases, including breast cancer. Caloric restriction has been shown to improve metabolic health and prolong lifespan, yet the molecular mechanisms underlying its long-term effects are not fully understood. In this study, we investigated the impact of long-term chronic (CCR) and intermittent caloric restriction (ICR) on the whole transcriptome of mammary fat pad tissue (MFP) in a breast cancer mouse model. Transgenic female Mouse Mammary Tumor Virus-Transforming Growth Factor-Alpha (MMTV-TGF-ɑ) C57BL/6 mice were randomized into ad libitum (AL), CCR, and ICR groups. Total RNA was isolated from the samples collected at weeks 10 (baseline), 49/50 (adult), and 81/82 (old), were then subjected to RNA sequencing. Differential gene expression analysis identified significant age-related transcriptomic shifts. Specifically, Malat1 expression levels, a long non-coding RNA associated with cancer progression, were elevated with aging, suggesting increased tumorigenic susceptibility in this model. Pathways linked to neuroendocrine signaling were downregulated with age, reflecting a potential decline in neuro-adipose cross-talk. Remarkably, ICR appeared to mitigate this age-related decline in neuroendocrine signaling by upregulating genes involved in neurotransmitter support and downregulating extracellular matrix organization and positive regulation of angiogenesis. In contrast, CCR did not effectively alter the whole transcriptome profile, particularly in long-term. Our findings reveal that ICR mitigates age-related transcriptional shifts in MFP tissue, providing a novel insight into dietary strategies for maintaining adipose tissue function with potential implications for cancer susceptibility.