Abstract
The “mechanistic target of rapamycin” (mTOR) is a central controller of growth, proliferation and/or motility of various cell-types ranging from adipocytes to immune cells, thereby linking metabolism and immunity. mTOR signaling is overactivated in obesity, promoting inflammation and insulin resistance. Therefore, great interest exists in the development of mTOR inhibitors as therapeutic drugs for obesity or diabetes. However, despite a plethora of studies characterizing the metabolic consequences of mTOR inhibition in rodent models, its impact on immune changes associated with the obese condition has never been questioned so far. To address this, we used a mouse model of high-fat diet (HFD)-fed mice with and without pharmacologic mTOR inhibition by rapamycin. Rapamycin was weekly administrated to HFD-fed C57BL/6 mice for 22 weeks. Metabolic effects were determined by glucose and insulin tolerance tests and by indirect calorimetry measures of energy expenditure. Inflammatory response and immune cell populations were characterized in blood, adipose tissue and liver. In parallel, the activities of both mTOR complexes (e. g. mTORC1 and mTORC2) were determined in adipose tissue, muscle and liver. We show that rapamycin-treated mice are leaner, have enhanced energy expenditure and are protected against insulin resistance. These beneficial metabolic effects of rapamycin were associated to significant changes of the inflammatory profiles of both adipose tissue and liver. Importantly, immune cells with regulatory functions such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were increased in adipose tissue. These rapamycin-triggered metabolic and immune effects resulted from mTORC1 inhibition whilst mTORC2 activity was intact. Taken together, our results reinforce the notion that controlling immune regulatory cells in metabolic tissues is crucial to maintain a proper metabolic status and, more generally, comfort the need to search for novel pharmacological inhibitors of the mTOR signaling pathway to prevent and/or treat metabolic diseases.
Highlights
The mechanistic target of rapamycin is a highly conserved serine-threonine kinase that regulates cell size, survival and proliferation in response to amino acids, growth factors, nutrients and cellular energy status [1]. mTOR signaling pathway is constitutively activated in obesity, leading to insulin resistance [2,3]
Consistent with body weight data, Rapa mice showed a significant reduction of visceral white adipose tissue (VWAT) mass, compared to controls (Figure 1B)
Mass of the brown adipose tissue (BAT; the major site of thermoregulation) was lower in Rapa mice (Figure 1B) and its histological analysis revealed less lipid accumulation (Figure 1H), suggesting that rapamycin treatment has increased thermogenesis. This was comforted by significant increased expression of genes involved in BAT function, namely uncoupling protein-1 (Ucp-1; a mitochondrial protein expressed in brown adipocytes that is involved in coldinduced nonshivering thermogenesis as well as diet-induced thermogenesis), carnitine palmitoyltransferase 1B (Cpt1b; a mitochondrial enzyme involved in fatty acid b-oxidation), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1a; a factor that controls several aspects of mitochondrial biogenesis and is essential in BAT thermogenesis and PR domain containing 16 (Prdm16; a zinc-finger protein highly enriched in brown adipocytes that is crucial in the control of brown fat determination), whereas Ucp-2 and Ucp-3 expression levels were comparable in both groups (Figure 1I)
Summary
The mechanistic (formerly mammalian) target of rapamycin (mTOR) is a highly conserved serine-threonine kinase that regulates cell size, survival and proliferation in response to amino acids, growth factors, nutrients and cellular energy status [1]. mTOR signaling pathway is constitutively activated in obesity, leading to insulin resistance [2,3]. The mTOR inhibitor rapamycin, an FDA-approved drug for patients with organ transplant [4] has been considered for treatment of metabolic disorders. MTORC1 is highly sensitive to the drug whilst only daily and chronic exposure to rapamycin can inhibit mTORC2 activity [6,7]. Conditional knockout of mTOR in the mouse model revealed its role in key functions of several metabolic tissues such as glycogen synthesis in muscle [8], ketogenesis and lipogenesis in the liver [9,10] and adipogenesis in the adipose tissue [11,12]. Treatment with rapamycin can reduce adiposity [13,14]. MTOR inhibition promotes the generation of CD4+ FoxP3+ regulatory T cells (Tregs) both in vitro and in vivo [21,22,23]
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