Verena Albert

mTOR in aging, metabolism, and cancer.

The target of rapamycin (TOR) is a highly conserved serine/threonine kinase that is part of two structurally and functionally distinct complexes, TORC1 and TORC2. In multicellular organisms, TOR regulates cell growth and metabolism in response to nutrients, growth factors and cellular energy. Deregulation of TOR signaling alters whole body metabolism and causes age-related disease. This review describes the most recent advances in TOR signaling with a particular focus on mammalian TOR (mTOR) in metabolic tissues vis-a-vis aging, obesity, type 2 diabetes, and cancer.

mTOR signaling in cellular and organismal energetics.

Mammalian TOR (mTOR) signaling controls growth, metabolism and energy homeostasis in a cell autonomous manner. Recent findings indicate that mTOR signaling in one tissue can also affect other organs thereby affecting whole body metabolism and energy homeostasis in a non-cell autonomous manner. It is thus not surprising that mTOR signaling mediates aging and is often deregulated in metabolic disorders, such as obesity, diabetes and cancer. This review discusses the regulation of cellular and whole body energy metabolism by mTOR, with particular focus on the non-cell autonomous function of mTOR.

Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21.

Significance The mammalian target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, growth factors, and cellular energy. Aberrant mTORC1 signaling is implicated in human diseases such as diabetes, obesity, and cancer. Our results reveal that ectopic mTORC1 activation in the liver controls the stress hormone fibroblast growth factor 21 (FGF21) in a peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α)–dependent manner via glutamine depletion, which in turn affects whole-body behavior and metabolism. mTORC1 signaling correlates with FGF21 expression in human liver tumors, suggesting that our findings in mice may have physiological relevance in glutamine-addicted human cancers. Thus, treatment with the anticancer drug rapamycin may have beneficial effects by blocking tumor growth and by preventing deregulation of whole-body physiology due to FGF21 expression. The liver is a key metabolic organ that controls whole-body physiology in response to nutrient availability. Mammalian target of rapamycin (mTOR) is a nutrient-activated kinase and central controller of growth and metabolism that is negatively regulated by the tumor suppressor tuberous sclerosis complex 1 (TSC1). To investigate the role of hepatic mTOR complex 1 (mTORC1) in whole-body physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice. L-Tsc1 KO mice displayed reduced locomotor activity, body temperature, and hepatic triglyceride content in a rapamycin-sensitive manner. Ectopic activation of mTORC1 also caused depletion of hepatic and plasma glutamine, leading to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α)–dependent fibroblast growth factor 21 (FGF21) expression in the liver. Injection of glutamine or knockdown of PGC-1α or FGF21 in the liver suppressed the behavioral and metabolic defects due to mTORC1 activation. Thus, mTORC1 in the liver controls whole-body physiology through PGC-1α and FGF21. Finally, mTORC1 signaling correlated with FGF21 expression in human liver tumors, suggesting that treatment of glutamine-addicted cancers with mTOR inhibitors might have beneficial effects at both the tumor and whole-body level.

mTORC2 sustains thermogenesis via Akt-induced glucose uptake and glycolysis in brown adipose tissue

Activation of non‐shivering thermogenesis (NST) in brown adipose tissue (BAT) has been proposed as an anti‐obesity treatment. Moreover, cold‐induced glucose uptake could normalize blood glucose levels in insulin‐resistant patients. It is therefore important to identify novel regulators of NST and cold‐induced glucose uptake. Mammalian target of rapamycin complex 2 (mTORC2) mediates insulin‐stimulated glucose uptake in metabolic tissues, but its role in NST is unknown. We show that mTORC2 is activated in brown adipocytes upon β‐adrenergic stimulation. Furthermore, mice lacking mTORC2 specifically in adipose tissue (AdRiKO mice) are hypothermic, display increased sensitivity to cold, and show impaired cold‐induced glucose uptake and glycolysis. Restoration of glucose uptake in BAT by overexpression of hexokinase II or activated Akt2 was sufficient to increase body temperature and improve cold tolerance in AdRiKO mice. Thus, mTORC2 in BAT mediates temperature homeostasis via regulation of cold‐induced glucose uptake. Our findings demonstrate the importance of glucose metabolism in temperature regulation.

Myopathy caused by mammalian target of rapamycin complex 1 (mTORC1) inactivation is not reversed by restoring mitochondrial function

Mammalian target of rapamycin complex 1 (mTORC1) is central to the control of cell, organ, and body size. Skeletal muscle-specific inactivation of mTORC1 in mice results in smaller muscle fibers, fewer mitochondria, increased glycogen stores, and a progressive myopathy that causes premature death. In mTORC1-deficient muscles, peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), which regulates mitochondrial biogenesis and glucose homeostasis, is strongly down-regulated. Here we tested whether induction of mitochondrial biogenesis pharmacologically or by the overexpression of PGC-1α is sufficient to reverse the phenotype of mice deficient for mTORC1. We show that both approaches normalize mitochondrial function, such as oxidative capacity and expression of mitochondrial genes. However, they do not prevent or delay the progressive myopathy. In addition, we find that mTORC1 has a much stronger effect than PGC-1α on the glycogen content in muscle. This effect is based on the strong activation of PKB/Akt in mTORC1-deficient mice. We also show that activation of PKB/Akt not only affects glycogen synthesis but also diminishes glycogen degradation. Thus, our work provides strong functional evidence that mitochondrial dysfunction in mice with inactivated mTORC1 signaling is caused by the down-regulation of PGC-1α. However, our data also show that the impairment of mitochondria does not lead directly to the lethal myopathy.

Rictor in Perivascular Adipose Tissue Controls Vascular Function by Regulating Inflammatory Molecule Expression

Objective—Perivascular adipose tissue (PVAT) wraps blood vessels and modulates vasoreactivity by secretion of vasoactive molecules. Mammalian target of rapamycin complex 2 (mTORC2) has been shown to control inflammation and is expressed in adipose tissue. In this study, we investigated whether adipose-specific deletion of rictor and thereby inactivation of mTORC2 in PVAT may modulate vascular function by increasing inflammation in PVAT. Approach and Results—Rictor, an essential mTORC2 component, was deleted specifically in mouse adipose tissue (rictorad−/−). Phosphorylation of mTORC2 downstream target Akt at Serine 473 was reduced in PVAT from rictorad−/− mice but unaffected in aortic tissue. Ex vivo functional analysis of thoracic aortae revealed increased contractions and impaired dilation in rings with PVAT from rictorad−/− mice. Adipose rictor knockout increased gene expression and protein release of interleukin-6, macrophage inflammatory protein-1&agr;, and tumor necrosis factor-&agr; in PVAT as shown by quantitative real-time polymerase chain reaction and Bioplex analysis for the cytokines in the conditioned media, respectively. Moreover, gene and protein expression of inducible nitric oxide synthase was upregulated without affecting macrophage infiltration in PVAT from rictorad−/− mice. Inhibition of inducible nitric oxide synthase normalized vascular reactivity in aortic rings from rictorad−/− mice with no effect in rictorfl/fl mice. Interestingly, in perivascular and epididymal adipose depots, high-fat diet feeding induced downregulation of rictor gene expression. Conclusions—Here, we identify mTORC2 as a critical regulator of PVAT-directed protection of normal vascular tone. Modulation of mTORC2 activity in adipose tissue may be a potential therapeutic approach for inflammation-related vascular damage.

Insulin resistance causes inflammation in adipose tissue

Obesity is a major risk factor for insulin resistance and type 2 diabetes. In adipose tissue, obesity-mediated insulin resistance correlates with the accumulation of proinflammatory macrophages and inflammation. However, the causal relationship of these events is unclear. Here, we report that obesity-induced insulin resistance in mice precedes macrophage accumulation and inflammation in adipose tissue. Using a mouse model that combines genetically induced, adipose-specific insulin resistance (mTORC2-knockout) and diet-induced obesity, we found that insulin resistance causes local accumulation of proinflammatory macrophages. Mechanistically, insulin resistance in adipocytes results in production of the chemokine monocyte chemoattractant protein 1 (MCP1), which recruits monocytes and activates proinflammatory macrophages. Finally, insulin resistance (high homeostatic model assessment of insulin resistance [HOMA-IR]) correlated with reduced insulin/mTORC2 signaling and elevated MCP1 production in visceral adipose tissue from obese human subjects. Our findings suggest that insulin resistance in adipose tissue leads to inflammation rather than vice versa.

Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice

Ketone bodies (KBs) are crucial energy substrates during states of low carbohydrate availability. However, an aberrant regulation of KB homeostasis can lead to complications such as diabetic ketoacidosis. Exercise and diabetes affect systemic KB homeostasis, but the regulation of KB metabolism is still enigmatic. In our study in mice with either knockout or overexpression of the peroxisome proliferator‐activated receptor‐γ coactivator (PGC)‐1α in skeletal muscle, PGC‐1α regulated ketolytic gene transcription in muscle. Furthermore, KB homeostasis of these mice was investigated during withholding of food, exercise, and ketogenic diet feeding, and after streptozotocin injection. In response to these ketogenic stimuli, modulation of PGC‐1α levels in muscle affected systemic KB homeostasis. Moreover, the data demonstrate that skeletal muscle PGC‐1α is necessary for the enhanced ketolytic capacity in response to exercise training and overexpression of PGC‐1α in muscle enhances systemic ketolytic capacity and is sufficient to ameliorate diabetic hyperketonemia in mice. In cultured myotubes, the transcription factor estrogen‐related receptor‐α was a partner of PGC‐1α in the regulation of ketolytic gene transcription. These results demonstrate a central role of skeletal muscle PGC‐1α in the transcriptional regulation of systemic ketolytic capacity.—Svensson, K., Albert, V., Cardel, B., Salatino, S., Handschin, C. Skeletal muscle PGC‐1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice. FASEB J. 30, 1976–1986 (2016). www.fasebj.org

Resveratrol and SRT1720 Elicit Differential Effects in Metabolic Organs and Modulate Systemic Parameters Independently of Skeletal Muscle Peroxisome Proliferator-activated Receptor γ Co-activator 1α (PGC-1α)

Background: Resveratrol and SRT1720 elicit beneficial metabolic effects, supposedly through activation of PGC-1α in skeletal muscle. Results: Resveratrol/SRT1720 differentially affect transcriptional regulation in metabolic organs and modulates systemic parameters independently of muscle PGC-1α. Conclusion: Skeletal muscle PGC-1α is largely dispensable for the systemic metabolic effects of resveratrol/SRT1720. Significance: Identifying molecular targets of resveratrol and SRT1720 is important to understand their therapeutic effect. Resveratrol (RSV) and SRT1720 (SRT) elicit beneficial metabolic effects and are postulated to ameliorate obesity and related metabolic complications. The co-activator, peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), has emerged as a major downstream effector responsible for metabolic remodeling of muscle and other metabolic tissues in response to RSV or SRT treatment. However, the requirement of PGC-1α in skeletal muscle for the systemic metabolic effects of these compounds has so far not been demonstrated. Using muscle-specific PGC-1α knock-out mice, we show that PGC-1α is necessary for transcriptional induction of mitochondrial genes in muscle with both RSV and SRT treatment. Surprisingly, the beneficial effects of SRT on glucose homeostasis and of both compounds on energy expenditure occur even in the absence of muscle PGC-1α. Moreover, RSV and SRT treatment elicit differential transcriptional effects on genes involved in lipid metabolism and mitochondrial biogenesis in liver and adipose tissue. These findings indicate that RSV and SRT do not induce analogous metabolic effects in vivo. Our results provide important insights into the mechanism, effects, and organ specificity of the caloric restriction mimetics RSV and SRT. These findings are important for the design of future therapeutic interventions aimed at ameliorating obesity and obesity-related metabolic dysfunction.

mTORC1 signaling in Agrp neurons mediates circadian expression of Agrp and NPY but is dispensable for regulation of feeding behavior.

Orexigenic agouti-related protein/neuropeptide Y (Agrp/NPY) neurons and an orexigenic pro-opiomelanocortin (POMC) neurons of the hypothalamus regulate feeding behavior and energy homeostasis. An understanding of the molecular signaling pathways that regulate Agrp/NPY and POMC function could lead to novel treatments for metabolic disorders. Target of Rapamycin Complex 1 (TORC1) is a nutrient-activated protein kinase and central controller of growth and metabolism. We therefore investigated the role of mammalian TORC1 (mTORC1) in Agrp neurons. We generated and characterized Agrp neuron-specific raptor knockout (Agrp-raptor KO) mice. Agrp-raptor KO mice displayed reduced, non-circadian expression of Agrp and NPY but normal feeding behavior and energy homeostasis on both normal and high fat diet. Thus, mTORC1 in Agrp neurons controls circadian expression of orexigenic neuropeptides but is dispensable for the regulation of feeding behavior and energy metabolism.