Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the ...mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.
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•Skeletal muscle-PGC-1α1 transgenic mice are resilient to stress-induced depression•PGC-1α1 induces skeletal muscle kynurenine aminotransferase (KAT) expression•Skeletal muscle PGC-1α1 controls plasma and brain kynurenine/kynurenic acid balance•Exercise training activates PGC-1α1:PPARα/δ:KAT in mouse and human skeletal muscle
Exercise training activates the PGC-1α1/PPARα/Δ pathway, increasing skeletal muscle expression of kynurenine aminotransferases that convert kynurenine to kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing the kynurenine burden protects the brain from stress-induced changes associated with depression.
Proteins of the peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1 (PGC-1) family of transcriptional coactivators coordinate physiological adaptations in many tissues, usually in ...response to demands for higher nutrient and energy supply. Of the founding members of the family,
PGC-1α
(also known as
PPARGC1A
) is the most highly regulated gene, using multiple promoters and alternative splicing to produce a growing number of coactivator variants.
PGC-1α
promoters are selectively active in distinct tissues in response to specific stimuli. To date, more than ten novel PGC-1α isoforms have been reported to be expressed from a novel promoter (PGC-1α-b, PGC-1α-c), to undergo alternative splicing (NT-PGC-1α) or both (PGC-1α2, PGC-1α3, PGC-1α4). The resulting proteins display differential regulation and tissue distribution and, most importantly, exert specific biological functions. In this review we discuss the structural and functional characteristics of the novel PGC-1α isoforms, aiming to provide an integrative view of this constantly expanding system of transcriptional coactivators.
The role of tryptophan-kynurenine metabolism in psychiatric disease is well established, but remains less explored in peripheral tissues. Exercise training activates kynurenine biotransformation in ...skeletal muscle, which protects from neuroinflammation and leads to peripheral kynurenic acid accumulation. Here we show that kynurenic acid increases energy utilization by activating G protein-coupled receptor Gpr35, which stimulates lipid metabolism, thermogenic, and anti-inflammatory gene expression in adipose tissue. This suppresses weight gain in animals fed a high-fat diet and improves glucose tolerance. Kynurenic acid and Gpr35 enhance Pgc-1α1 expression and cellular respiration, and increase the levels of Rgs14 in adipocytes, which leads to enhanced beta-adrenergic receptor signaling. Conversely, genetic deletion of Gpr35 causes progressive weight gain and glucose intolerance, and sensitizes to the effects of high-fat diets. Finally, exercise-induced adipose tissue browning is compromised in Gpr35 knockout animals. This work uncovers kynurenine metabolism as a pathway with therapeutic potential to control energy homeostasis.
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•Kynurenic acid increases energy expenditure by activating Gpr35•Gpr35 activation improves energy metabolism and inflammation in mice fed a high-fat diet•Kynurenic acid enhances adipocyte beta-adrenergic receptor signaling through Rgs14•Gpr35 knockout compromises exercise-induced adipose tissue browning
Kynurenine is a neurotoxic metabolite detoxified to kynurenic acid by exercised skeletal muscle. Now, Agudelo et al. show that the rise in circulating kynurenic acid activates Gpr35 in adipose tissue and increases energy expenditure. This improves the metabolic consequences of high-fat diet feeding in mice. Gpr35 deletion causes progressive weight gain.
Fibroblast growth factor 21 (FGF21) is active in murine adipocytes and has beneficial metabolic effects in animal models of type 2 diabetes mellitus. We assessed whether FGF21 influences lipolysis in ...human adipocytes and 3T3-L1 cells. FGF21 had no short-time effect (h) while a 3-day incubation with FGF21 attenuated hormone-stimulated lipolysis. FGF21 did not influence the mRNA expression of genes involved in regulating lipolysis, but significantly reduced the expression of the lipid droplet-associated phosphoprotein perilipin without affecting differentiation. Via reduced release of fatty acids into the circulation, the anti-lipolytic effect could be a mechanism through which FGF21 promotes insulin sensitivity in man.
Skeletal muscle mass and strength are crucial determinants of health. Muscle mass loss is associated with weakness, fatigue, and insulin resistance. In fact, it is predicted that controlling muscle ...atrophy can reduce morbidity and mortality associated with diseases such as cancer cachexia and sarcopenia.
We analyzed gene expression data from muscle of mice or human patients with diverse muscle pathologies and identified LMCD1 as a gene strongly associated with skeletal muscle function. We transiently expressed or silenced LMCD1 in mouse gastrocnemius muscle or in mouse primary muscle cells and determined muscle/cell size, targeted gene expression, kinase activity with kinase arrays, protein immunoblotting, and protein synthesis levels. To evaluate force, calcium handling, and fatigue, we transduced the flexor digitorum brevis muscle with a LMCD1-expressing adenovirus and measured specific force and sarcoplasmic reticulum Ca
release in individual fibers. Finally, to explore the relationship between LMCD1 and calcineurin, we ectopically expressed Lmcd1 in the gastrocnemius muscle and treated those mice with cyclosporine A (calcineurin inhibitor). In addition, we used a luciferase reporter construct containing the myoregulin gene promoter to confirm the role of a LMCD1-calcineurin-myoregulin axis in skeletal muscle mass control and calcium handling.
Here, we identify LIM and cysteine-rich domains 1 (LMCD1) as a positive regulator of muscle mass, that increases muscle protein synthesis and fiber size. LMCD1 expression in vivo was sufficient to increase specific force with lower requirement for calcium handling and to reduce muscle fatigue. Conversely, silencing LMCD1 expression impairs calcium handling and force, and induces muscle fatigue without overt atrophy. The actions of LMCD1 were dependent on calcineurin, as its inhibition using cyclosporine A reverted the observed hypertrophic phenotype. Finally, we determined that LMCD1 represses the expression of myoregulin, a known negative regulator of muscle performance. Interestingly, we observed that skeletal muscle LMCD1 expression is reduced in patients with skeletal muscle disease.
Our gain- and loss-of-function studies show that LMCD1 controls protein synthesis, muscle fiber size, specific force, Ca
handling, and fatigue resistance. This work uncovers a novel role for LMCD1 in the regulation of skeletal muscle mass and function with potential therapeutic implications.
Twist1 in Human White Adipose Tissue and Obesity Pettersson, Amanda T; Mejhert, Niklas; Jernås, Margareta ...
The journal of clinical endocrinology and metabolism,
01/2011, Letnik:
96, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Context: Twist1 is a transcription factor implicated in the regulation of TNFα signaling and was recently shown to be highly expressed in both human and murine adipose tissue, but its role in obesity ...is unknown.
Objective: Our objective was to assess the expression of twist1 in human white adipose tissue (WAT), its relationship to obesity and insulin sensitivity, and how it modifies TNFα-mediated inflammation in adipocytes.
Procedure: Twist mRNA levels were measured in WAT from 130 nonobese and obese subjects, and its relation to clinical parameters was assessed. Twist1 expression was measured before and after weight loss as well as in different adipose regions. Human in vitro differentiated adipocytes were treated with TNFα under control conditions or after twist1 gene silencing by RNA interference. Gene expression and secretion of proinflammatory proteins were measured.
Results: Twist1 expression was low in obese subjects and increased after weight loss. Twist1 mRNA levels correlated with adiponectin levels and inversely with insulin resistance as well as adipocyte volume (P < 0.001 for all). Low twist1 expression associated with a hypertrophic adipose tissue and high secretion of TNFα and monocyte chemoattractant protein-1 from WAT. Finally, twist1 silencing in human adipocytes enhanced TNFα-induced monocyte chemoattractant protein-1 expression and secretion, which was paralleled by an increase in the mRNA expression of the nuclear factor-κB gene RelA.
Conclusions: Low twist1 expression in human WAT correlates with obesity and an insulin-resistant phenotype, which may be mediated by an increased sensitivity to the proinflammatory effect of TNFα.
Low twist1 expression in human white adipose tissue associates with obesity, insulin resistance, and hypertrophic adipose tissue, and augments TNFα-stimulated monocyte chemoattractant protein-1 secretion.
Context: Fibroblast growth factors (FGFs) regulate the development of white adipose tissue (WAT). However, the secretion and cellular origin of individual FGFs in WAT as well as the influence of ...obesity are unknown.
Objective: Our objective was to map FGFs in human sc WAT, the cellular source, and association with obesity.
Design: Secretion, mRNA, and circulatory levels of FGFs in human abdominal sc WAT from nonobese and obese donors were examined by microarray, real-time quantitative PCR, and ELISA. The activity of FGFs in cultured human adipocytes was determined by phosphorylation assays.
Results: Expression of five FGFs (FGF1, FGF2, FGF7, FGF9, and FGF18) and FGF homologous factor (FHF2) was identified in WAT. Only FGF1 was released in a time-dependent manner from sc WAT, and fat cells were the major source of FGF1 secretion. FGF1 expression increased and FGF2 decreased during adipocyte differentiation. Furthermore, FGF1 was not secreted into the circulation. Although FGF1 levels were 2-fold increased in obesity, they were unaltered by weight reduction. Only FGF1 and FGF2 induced a marked concentration-dependent phosphorylation of p44/42 in cultured human adipocytes.
Conclusions: Of the investigated FGFs, only FGF1 is secreted from sc WAT and predominantly so from the adipocyte fraction. The activity in adipocyte cultures and lack of secretion into the circulation suggest that FGF1 acts as an auto- or paracrine factor. FGF1 levels are increased in obesity but unaffected by weight reduction, suggesting a primary defect in obese individuals. In conclusion, FGF1 may play a superior role among the FGFs in sc WAT and obesity development.
Of the investigated FGFs, only FGF1 is secreted from human subcutaneous adipocytes and the production is increased in obesity but not influenced by weight-loss.
The liver X receptors (LXRs) play a key role in cholesterol and bile acid metabolism but are also important regulators of glucose metabolism. Recently, LXRs have been proposed as a glucose sensor ...affecting LXR-dependent gene expression. We challenged wild-type (WT) and LXRαβ(-/-) mice with a normal diet (ND) or a high-carbohydrate diet (HCD). Magnetic resonance imaging showed different fat distribution between WT and LXRαβ(-/-) mice. Surprisingly, gonadal (GL) adipocyte volume decreased on HCD compared with ND in WT mice, whereas it slightly increased in LXRαβ(-/-) mice. Interestingly, insulin-stimulated lipogenesis of isolated GL fat cells was reduced on HCD compared with ND in LXRαβ(-/-) mice, whereas no changes were observed in WT mice. Net de novo lipogenesis (DNL) calculated from Vo(2) and Vco(2) was significantly higher in LXRαβ(-/-) than in WT mice on HCD. Histology of HCD-fed livers showed hepatic steatosis in WT mice but not in LXRαβ(-/-) mice. Glucose tolerance was not different between groups, but insulin sensitivity was decreased by the HCD in WT but not in LXRαβ(-/-) mice. Finally, gene expression analysis of adipose tissue showed induced expression of genes involved in DNL in LXRαβ(-/-) mice compared with WT animals as opposed to the liver, where expression of DNL genes was repressed in LXRαβ(-/-) mice. We thus conclude that absence of LXRs stimulates DNL in adipose tissue, but suppresses DNL in the liver, demonstrating opposite roles of LXR in DNL regulation in these two tissues. These results show tissue-specific regulation of LXR activity, a crucial finding for drug development.
Liver X receptors (LXRs) are nuclear receptors with established roles in cholesterol, lipid, and carbohydrate metabolism, although their function in adipocytes is not well characterized. Increased ...adipose tissue mass in obesity is associated with increased adipocyte lipolysis. Fatty acids (FA) generated by lipolysis can be oxidized by mitochondrial β-oxidation, reesterified, or released from the adipocyte. The latter results in higher circulating levels of free FAs, in turn causing obesity-related metabolic complications. However, mitochondrial β-oxidation can at least in part counteract an increased output of FA into circulation. In this study, we provide evidence that activation of LXRs up-regulates mitochondrial β-oxidation in both human and murine white adipocytes. We also show that the expression of a kinase regulating the cellular fuel switch, pyruvate dehydrogenase kinase 4 (PDK4), is up-regulated by the LXR agonist GW3965 in both in vitro differentiated human primary adipocytes and differentiated murine 3T3-L1 cells. Moreover, activation of LXR causes PDK4-dependent phosphorylation of the pyruvate dehydrogenase complex, thereby decreasing its activity and attenuating glucose oxidation. The specificity of the GW3965 effect on oxidation was confirmed by RNA interference targeting LXRs. We propose that LXR has an important role in the regulation of substrate oxidation and the switch between lipids and carbohydrates as cellular fuel in both human and murine white adipocytes.
Activation of liver X receptor (LXR) in human adipocytes suppresses glucose oxidation and increases fatty acid oxidation by regulating activity of the pyruvate dehydrogenase complex.
Twist1 is a transcription factor that is highly expressed in murine brown and white adipose tissue (WAT) and negatively regulates fatty acid oxidation in mice. The role of twist1 in WAT is not known ...and was therefore examined.
The expression of twist1 was determined by quantitative real-time PCR in different tissues and in different cell types within adipose tissue. The effect of twist1 small interfering RNA on fatty acid oxidation, lipolysis, adipokine secretion, and mRNA expression was determined in human adipocytes. The interaction between twist1 and specific promoters in human adipocytes was investigated by chromatin immunoprecipitation (ChIP) and reporter assays.
Twist1 was highly expressed in human WAT compared with a set of other tissues and found predominantly in adipocytes. Twist1 levels increased during in vitro differentiation of human preadipocytes. Gene silencing of twist1 in human white adipocytes had no effect on lipolysis or glucose transport. Unexpectedly, and in contrast with results in mice, twist1 RNA interference reduced fatty acid oxidation. Furthermore, the expression and secretion of the inflammatory factors tumor necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein-1 were downregulated by twist1 silencing. ChIP and reporter assays confirmed twist1 interaction with the promoters of these genes.
Twist1 may play a role in inflammation of human WAT because it can regulate the expression and secretion of inflammatory adipokines via direct transcriptional effects in white adipocytes. Furthermore, twist1 may, in contrast to findings in mice, be a positive regulator of fatty acid oxidation in human white adipocytes.
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