Interferon regulatory factor 4 dictates metabolic flexibility of fat versus muscle loss during repeated intermittent fasting
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abstract
Interferon regulatory factor 4 (IRF4) is a transcription factor that regulates the proliferation, differentiation, and metabolism of immune cells, such as macrophages and T cells. Recently, IRF4 has been shown to regulate lipolysis in adipocytes and increases in visceral human adipose tissue and murine white adipose tissue during acute fasting. However, it was unknown how IRF4 influences metabolic responses to repeated intermittent fasting. We hypothesized that blunted lipolysis, caused by Irf4 deletion, would promote altered metabolic substrate selection, specifically amino acids from muscle as opposed to fatty acids and glycerol from fat, to maintain energy homeostasis during repeated fasting in mice. Littermate whole body and adipocyte specific Irf4 knockout mice were placed on a 45% kcal from fat diet and either left to consume food ad-libitum or put on a 5:2 repeated fasting protocol for 10 weeks, which consisted of two 24-hour fast periods on non-consecutive days of the week. Body composition measures, using MRI, showed that littermate wild type mice lost more body and fat mass compared to Irf4 knockout mice during the fasting protocol. In line with our hypothesis, Irf4 knockout mice lost significantly more lean mass compared to wild-type mice. In conjunction with our MRI data, the Irf4 knockout mice had lower hindlimb, tibialis anterior muscle mass along with higher gonadal and inguinal white adipose tissue mass after the fasting protocol compared to the wild type mice. Additionally, we found that adipocyte-specific deletion of Irf4 recapitulated these effects on muscle and fat mass during intermittent fasting. We then used metabolic cages to examine energy expenditure and fuel oxidation. Complementary to our previous data, adipocyte-specific Irf4 knockout mice had lower fatty acid oxidation and higher carbohydrate oxidation rates compared to the wild type mice. Since adipocyte-specific Irf4 knockout mice have blunted lipolysis and lower fatty acid oxidation rates, our data suggests that another metabolic fuel source, specifically muscle protein, is being used to maintain energy homeostasis during fasting. Collectively, our data highlights a novel metabolic role for IRF4 in mediating fasting-dependent changes in body composition, specifically the balance between fat and muscle mass during repeated intermittent fasting. CIHR, NSERC, CFI, and Diabetes Canada This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
