Abstract
Aging and obesity are common risk factors for numerous chronic pathologies, and the compounding effects of old age and increased adiposity pose a serious threat to public health. Starting from the assumption that aging and obesity may have shared underpinnings, we investigated the antiobesogenic potential of a successful longevity intervention, the mTORC1 inhibitor rapamycin. We find that rapamycin prevents diet-induced obesity in mice and increases the activity of C/EBP-β LAP, a transcription factor that regulates the metabolic shift to lipid catabolism observed in response to calorie restriction. Independent activation of C/EBP-β LAP with the antiretroviral drug adefovir dipivoxil recapitulates the anti-obesogenic effects of rapamycin without reducing signaling through mTORC1 and increases markers of fat catabolism in the liver. Our findings support a model that C/EBP-β LAP acts downstream of mTORC1 signaling to regulate fat metabolism and identifies a novel drug that may be exploited to treat obesity and decrease the incidence of age-related disease.
Highlights
The rate of obesity has been rising sharply in industrialized countries, especially in the United States (Hales et al, 2020), and poses a serious threat to already overburdened healthcare systems (Finkelstein et al, 2009; Cawley and Meyerhoefer, 2012)
Based on the previously described role of mTOR complex 1 (mTORC1) in C/EBPβ regulation, we investigated whether rapamycin increased expression of C/EBP-β targets in the livers of female mice fed a HFD via western blot
We provide evidence that inhibiting mTORC1 protects against diet-induced obesity by activating fatty acid catabolism through C/EBP-β
Summary
The rate of obesity has been rising sharply in industrialized countries, especially in the United States (Hales et al, 2020), and poses a serious threat to already overburdened healthcare systems (Finkelstein et al, 2009; Cawley and Meyerhoefer, 2012). The greatest risk factor for most of these diseases is old age (Kaeberlein, 2013), and obese older individuals are at even greater risk than either group alone (Samper-Ternent and Al Snih, 2012). The field of geroscience seeks to understand mechanisms that connect biological aging with agerelated pathologies (Kennedy et al, 2014; Sierra, 2016). Several therapeutic approaches that target the molecular hallmarks of biological aging have been shown to increase lifespan and delay age-related pathologies in mice (Kaeberlein, 2017). Inhibition of the mechanistic target of rapamycin (mTOR) has proven robust and reproducible (Johnson et al, 2013; Kennedy and Lamming, 2016).
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