| Summary: | <b>: </b>The molecular adaptations that underpin body composition changes and health benefits of intermittent fasting (IF) and high-intensity interval training (HIIT) are unclear. The present study investigated these adaptations within the hypothalamus, white adipose and skeletal muscle tissue following 12 weeks of IF and/or HIIT in diet-induced obese mice. Mice (C57BL/6, 8-week-old, males/females) were fed high-fat (59%) and sugar (30%) water (HF/S) for 12 weeks followed by an additional 12 weeks of HF/S plus either IF, HIIT, combination (IF+HIIT) or HF/S only control (CON). Tissues were harvested at 12 and 24 weeks and analysed for various molecular markers. Hypothalamic <i>NP</i><i>Y</i> expression was significantly lower following IF+HIIT compared to CON in females. In adipose tissue, leptin expression was significantly lower following IF and IF+HIIT compared to CON in males and females. Males demonstrated increased markers of fat oxidation (<i>HADH</i>, <i>FABP4</i>) following IF+HIIT, whereas females demonstrated reduced markers of adipocyte differentiation/storage (<i>CIDEC</i> and <i>FOXO1</i>) following IF and/or IF+HIIT. In muscle, <i>SIRT1</i>, <i>UCP3, PGC1α</i>, and <i>AS160</i> expression was significantly lower following IF compared to CON in males and/or females. This investigation suggests that males and females undertaking IF and HIIT may prevent weight gain via different mechanisms within the same tissue.
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