Regulation Of Metabolic Functions Research Articles

Research Resource: Tissue- and Pathway-Specific Metabolomic Profiles of the Steroid Receptor Coactivator (SRC) Family

The rapidly growing family of transcriptional coregulators includes coactivators that promote transcription and corepressors that harbor the opposing function. In recent years, coregulators have emerged as important regulators of metabolic homeostasis, including the p160 steroid receptor coactivator (SRC) family. Members of the SRC family have been ascribed important roles in control of gluconeogenesis, fat absorption and storage in the liver, and fatty acid oxidation in skeletal muscle. To provide a deeper and more granular understanding of the metabolic impact of the SRC family members, we performed targeted metabolomic analyses of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice with global knockouts (KOs) of SRC-1, SRC-2, or SRC-3. We measured amino acids, acyl carnitines, and organic acids in five tissues with key metabolic functions (liver, heart, skeletal muscle, brain, plasma) isolated from SRC-1, -2, or -3 KO mice and their wild-type littermates under fed and fasted conditions, thereby unveiling unique metabolic functions of each SRC. Specifically, SRC-1 ablation revealed the most significant impact on hepatic metabolism, whereas SRC-2 appeared to impact cardiac metabolism. Conversely, ablation of SRC-3 primarily affected brain and skeletal muscle metabolism. Surprisingly, we identified very few metabolites that changed universally across the three SRC KO models. The findings of this Research Resource demonstrate that coactivator function has very limited metabolic redundancy even within the homologous SRC family. Furthermore, this work also demonstrates the use of metabolomics as a means for identifying novel metabolic regulatory functions of transcriptional coregulators.

Inhibition of CTRP9, a novel and cardiac-abundantly expressed cell survival molecule, by TNFα-initiated oxidative signaling contributes to exacerbated cardiac injury in diabetic mice

Recently identified as adiponectin (APN) paralogs, C1q/TNF-related proteins (CTRPs) share similar metabolic regulatory functions as APN. The current study determined cardiac expression of CTRPs, their potential cardioprotective function, and investigated whether and how diabetes may regulate cardiac CTRP expression. Several CTRPs are expressed in the heart at levels significantly greater than APN. Most notably, cardiac expression of CTRP9, the closest paralog of APN, exceeds APN by >100-fold. Cardiac CTRP9 expression was significantly reduced in high-fat diet-induced diabetic mice. In H9c2 cells, tumor necrosis factor-alpha (TNF-α) strongly inhibited CTRP9 expression (>60%), and significantly reduced peroxisome proliferator activated receptor-gamma (PPARγ), a known transcription factor promoting adiponectin expression. The inhibitory effect of TNF-α on PPARγ and CTRP9 was reversed by Tiron or rosiglitazone. CTRP9 knockdown significantly enhanced, whereas CTRP9 overexpression significantly attenuated simulated ischemia/reperfusion injury in H9c2 cells. In vivo CTRP9 administration to diabetic mice significantly attenuated NADPH oxidase expression and superoxide generation, reduced infarct size, and improved cardiac function. To the best of our knowledge, this is the first study providing evidence that downregulation of CTRP9, an abundantly expressed and novel cell survival molecule in the heart, by TNF-α-initiated oxidative PPARγ suppression contributes to exacerbated diabetic cardiac injury. Preservation of CTRP9 expression or augmentation of CTRP9-initiated signaling mechanisms may be the potential avenues for ameliorating ischemic diabetic cardiac injury.

Transcriptional Regulation of Plant Secondary MetabolismF

Plant secondary metabolites play critical roles in plant-environment interactions. They are synthesized in different organs or tissues at particular developmental stages, and in response to various environmental stimuli, both biotic and abiotic. Accordingly, corresponding genes are regulated at the transcriptional level by multiple transcription factors. Several families of transcription factors have been identified to participate in controlling the biosynthesis and accumulation of secondary metabolites. These regulators integrate internal (often developmental) and external signals, bind to corresponding cis-elements--which are often in the promoter regions--to activate or repress the expression of enzyme-coding genes, and some of them interact with other transcription factors to form a complex. In this review, we summarize recent research in these areas, with an emphasis on newly-identified transcription factors and their functions in metabolism regulation.

Metabolic rate regulation by the renin–angiotensin system: brain vs. body

Substantial evidence supports a role for the renin-angiotensin system (RAS) in the regulation of metabolic function, but an apparent paradox exists where genetic or pharmacological inhibition of the RAS occasionally has similar physiological effects as chronic angiotensin infusion. Similarly, while RAS targeting in animal models has robust metabolic consequences, effects in humans are more subtle. Here, we review the data supporting a role for the RAS in metabolic rate regulation and propose a model where the local brain RAS works in opposition to the peripheral RAS, thus helping to explain the paradoxically similar effects of RAS supplementation and inhibition. Selectively modulating the peripheral RAS or brain RAS may thus provide a more effective treatment paradigm for obesity and obesity-related disorders.

The Nuclear Receptor, Nor-1, Markedly Increases Type II Oxidative Muscle Fibers and Resistance to Fatigue

Nuclear hormone receptors (NR) have been implicated as regulators of lipid and carbohydrate metabolism. The orphan NR4A subgroup has emerged as regulators of metabolic function. Targeted silencing of neuron-derived orphan receptor 1 (Nor-1)/NR4A3 in skeletal muscle cells suggested that this NR was necessary for oxidative metabolism in vitro. To investigate the in vivo role of Nor-1, we have developed a mouse model with preferential expression of activated Nor-1 in skeletal muscle. In skeletal muscle, this resulted in a marked increase in: 1) myoglobin expression, 2) mitochondrial DNA and density, 3) oxidative enzyme staining, and 4) genes/proteins encoding subunits of electron transport chain complexes. This was associated with significantly increased type IIA and IIX myosin heavy chain mRNA and proteins and decreased type IIB myosin heavy chain mRNA and protein. The contractile protein/fiber type remodeling driving the acquisition of the oxidative type II phenotype was associated with 1) the significantly increased expression of myocyte-specific enhancer factor 2C, and phospho-histone deacetylase 5, and 2) predominantly cytoplasmic HDAC5 staining in the Tg-Nor-1 mice. Moreover, the Nor-1 transgenic line displayed significant improvements in glucose tolerance, oxygen consumption, and running endurance (in the absence of increased insulin sensitivity), consistent with increased oxidative capacity of skeletal muscle. We conclude that skeletal muscle fiber type is not only regulated by exercise-sensitive calcineurin-induced signaling cascade but also by NR signaling pathways that operate at the nexus that coordinates muscle performance and metabolic capacity in this major mass tissue.

Thermoregulation: An Orphan Receptor Finds Its Way in the Cold

The hypometabolic state of torpor is a widely utilized and well-orchestrated response to food shortage. A new study shows that the melatonin-related orphan receptor GPR50 plays an important function in metabolic regulation for entry into torpor.

Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism

It is well known that ErbB2, a receptor tyrosine kinase, localizes on the plasma membrane. Here we describe a novel observation that ErbB2 also localizes in mitochondria of cancer cells and patient samples. We found that ErbB2 translocates into mitochondria through the association with mtHSP70. Additionally, mitochondrial ErbB2 (mtErbB2) negatively regulates mitochondrial respiratory functions. Oxygen consumption and activities of complexes of the mitochondrial electron transport chain were decreased in mtErbB2-overexpressing cells. Mitochondrial membrane potential and the cellular ATP level also were decreased. In contrast, mtErbB2 enhanced cellular glycolysis. The translocation of ErbB2 and its impact on mitochondrial function are kinase dependent. Interestingly, cancer cells with higher levels of mtErbB2 were more resistant to ErbB2 targeting antibody trastuzumab. Our study provides a novel perspective on the metabolic regulatory function of ErbB2 and reveals that mtErbB2 plays an important role in the regulation of cellular metabolism and cancer cell resistance to therapeutics.

Can vitamin D slow down the progression of chronic kidney disease?

Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone of renoprotective therapy, and the reduction of persistent RAAS activation is considered to be an important target in the treatment of chronic kidney disease (CKD). Vitamin D is a steroid hormone that controls a broad range of metabolic and cell regulatory functions. It acts as a transcription factor and can suppress the renin gene, thereby acting as a negative endocrine regulator of RAAS. RAAS activation can reduce renal Klotho expression, and the Klotho-fibroblast growth factor 23 interaction may further reduce the production of active vitamin D. Results from both clinical and experimental studies suggest that vitamin D therapy is associated with a reduction in blood pressure and left ventricular hypertrophy and improves cardiovascular outcomes. In addition, a reduction in angiotensin II through RAAS blockade may have anti-proteinuric and anti-fibrotic effects. Vitamin D has also been shown to modulate the immune system, regulate inflammatory responses, improve insulin sensitivity and reduce high-density lipoprotein cholesterol. Taken together, these pleiotropic effects of vitamin D may slow down the progression of CKD. In this review, we discuss the experimental and early clinical findings that suggest a renoprotective effect of vitamin D, thereby providing an additional rationale beyond mineral metabolism for the close monitoring of, and supplementation with vitamin D from the earliest stages of CKD.

Abstract 8966: C1q/TNF-Related Proteins (CTRPs), a Family of Novel Adipokines, Induce Vascular Relaxation through the Adiponectin Receptor-1/AMPK/eNOS/Nitric Oxide Signaling Pathway

Reduced plasma adiponectin (APN) in diabetic patients is associated with endothelial dysfunction and vascular injury. However, APN knockout animals manifest only modest systemic dysfunction unless metabolically challenged. The CTRP (C1q/TNF-related proteins) family has recently been identified as APN paralogs. Some CTRP members share APN’s metabolic regulatory function. However, the vascular biology of CTRPs remains completely unknown. This study assessed the vasoactivity of currently identified murine CTRP members utilizing in vitro and in vivo experimental models, and elucidated underlying molecular mechanisms in HUVECs. Of eight CTRPs investigated, three CTRPs (3, 5, and 9) caused significant vasorelaxation in concentration-dependent fashion, while the remaining CTRPs neither constricted nor dilated aortic segments. The vasodilatory potency of CTRP9 exceeded that of APN (3-fold), is endothelium-dependent, and mediated by nitric oxide (NO). Plasma CTRP9 levels were markedly increased in APN knockout mice, and significantly reduced in high-fat-diet induced obesity/diabetic mice (P<0.05). One week of in vivo CTRP9 administration initiated after 3 weeks high-fat-diet, at a dose restoring physiological CTRP9 levels, significantly improved vascular endothelial function (P<0.01). Mechanistically, CTRP9 increased AMPK/Akt/eNOS phosphorylation and increased endothelial NO production. AMPK knockdown completely blocked CTRP9-induced Akt/eNOS phosphorylation and NO production. Akt knockdown had no significant effect upon CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1 (AdipoR1), but not receptor 2 (AdipoR2), knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, pre-incubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasodilatory effects. Collectively, we have provided the first evidence that CTRP9 is a novel vasodilatory/vasculoprotective adipokine, potentially compensatory for APN’s vascular effects in APN knockout animals. Moreover, we have demonstrated that CTRP9 exerts its vascular biological effects via the AdipoR1/AMPK/eNOS dependent/NO mediated signaling pathway.

Proatherogenic Abnormalities of Lipid Metabolism in SirT1 Transgenic Mice Are Mediated through Creb Deacetylation

Dyslipidemia and atherosclerosis are associated with reduced insulin sensitivity and diabetes, but the mechanism is unclear. Gain of function of the gene encoding deacetylase SirT1 improves insulin sensitivity and could be expected to protect against lipid abnormalities. Surprisingly, when transgenic mice overexpressing SirT1 (SirBACO) are placed on atherogenic diet, they maintain better glucose homeostasis, but develop worse lipid profiles and larger atherosclerotic lesions than controls. We show that transcription factor cAMP response element binding protein (Creb) is deacetylated in SirBACO mice. We identify Lys136 is a substrate for SirT1-dependent deacetylation that affects Creb activity by preventing its cAMP-dependent phosphorylation, leading to reduced expression of glucogenic genes and promoting hepatic lipid accumulation and secretion. Expression of constitutively acetylated Creb (K136Q) in SirBACO mice mimics Creb activation and abolishes the dyslipidemic and insulin-sensitizing effects of SirT1 gain of function. We propose that SirT1-dependent Creb deacetylation regulates the balance between glucose and lipid metabolism, integrating fasting signals.

CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability.

The nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase SIRT1 is a major metabolic regulator activated by energy stresses such as fasting or calorie restriction. SIRT1 activation during fasting not only relies on the increase in the NAD(+)/NADH ratio caused by energy deprivation but also involves an upregulation of SIRT1 mRNA and protein levels in various metabolic tissues. We demonstrate that SIRT1 expression is controlled systemically by the activation of the cyclic AMP response-element-binding protein upon low nutrient availability. Conversely, in the absence of energetic stress, the carbohydrate response-element-binding protein represses the expression of SIRT1. Altogether, these results demonstrate that SIRT1 expression is tightly controlled at the transcriptional level by nutrient availability and further underscore that SIRT1 is a crucial metabolic checkpoint connecting the energetic status with transcriptional programmes.

C1q/TNF-Related Proteins, A Family of Novel Adipokines, Induce Vascular Relaxation Through the Adiponectin Receptor-1/AMPK/eNOS/Nitric Oxide Signaling Pathway

Reduced plasma adiponectin (APN) in diabetic patients is associated with endothelial dysfunction. However, APN knockout animals manifest modest systemic dysfunction unless metabolically challenged. The protein family CTRPs (C1q/TNF-related proteins) has recently been identified as APN paralogs and some CTRP members share APN's metabolic regulatory function. However, the vasoactive properties of CTRPs remain completely unknown. The vasoactivity of currently identified murine CTRP members was assessed in aortic vascular rings and underlying molecular mechanisms was elucidated in human umbilical vein endothelial cells. Of 8 CTRPs, CTRPs 3, 5, and 9 caused significant vasorelaxation. The vasoactive potency of CTRP9 exceeded that of APN (3-fold) and is endothelium-dependent and nitric oxide (NO)-mediated. Mechanistically, CTRP9 increased AMPK/Akt/eNOS phosphorylation and increased NO production. AMPK knockdown completely blocked CTRP9-induced Akt/eNOS phosphorylation and NO production. Akt knockdown had no significant effect on CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1, but not receptor 2, knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, preincubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasorelaxative effects. We have provided the first evidence that CTRP9 is a novel vasorelaxative adipocytokine that may exert vasculoprotective effects via the adiponectin receptor 1/AMPK/eNOS dependent/NO mediated signaling pathway.

Exotic fruits as therapeutic complements for diabetes, obesity and metabolic syndrome

The prevalence and severity of obesity, type 2-diabetes, and the resultant metabolic syndrome are rapidly increasing. As successful preventive and therapeutic strategies for these life-threatening health ailments often come with adverse side effects, nutritional elements are widely used in many countries as preventive therapies to prevent or manage metabolic syndrome. Fruits are important dietary components, and contain various bioactive constituents. Many of these constituents have been proven to be useful to manage and treat various chronic diseases such as diabetes, obesity, cancer and cardiovascular diseases. Although exotic fruits are understudied throughout the world due to their limited regional presence, many studies reveal their potent ability to ameliorate metabolic derangements and the resultant conditions i.e. diabetes and obesity. The aim of this article is to review the role of exotic fruits and their constituents in the regulation of metabolic functions, which can beneficially alter diabetes and obesity pathophysiology.

Adipokines in inflammation and metabolic disease.

The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.

Alpha-Melanocyte stimulating hormone: production and degradation

Proopiomelanocortin (POMC) is a polypeptide hormone precursor that is expressed in the brain and in peripheral tissues such as in the pituitary gland, immune system, and skin. In the brain, POMC is processed to form several peptides including alpha-melanocyte stimulating hormone (α-MSH). alpha-MSH is expressed in the hypothalamic arcuate nucleus and in the nucleus tractus solitarius of the brainstem where it has a crucial role in the regulation of metabolic functions. Specifically, α-MSH is an anorexigenic peptide. Its production and maturation processes have been shown to be regulated according to the metabolic condition of the organism. This review summarizes our current knowledge on α-MSH processing including its maturation and degradation processes and pharmacological aspects of its manipulation.

Metabolic and nonmetabolic regulatory functions of peroxisome proliferator-activated receptor β

This review focuses on the emerging knowledge about peroxisome proliferator-activated receptor beta regulatory functions on metabolism, inflammation, and cellular stress. Recent publications have confirmed the important roles of peroxisome proliferator-activated receptor beta in adaptive metabolic responses of skeletal muscle and have also implicated the nuclear receptor in the regulation of inflammation and oxidative stress in various tissues. The mechanisms implicated in these effects have been partially elucidated. Peroxisome proliferator-activated receptors mediate the transcriptional effects of fatty acids and fatty acid derivatives and regulate many physiological functions, including metabolism and development. Use of potent and specific agonists revealed that activation of peroxisome proliferator-activated receptor beta efficiently reverses some metabolic syndrome-associated abnormalities by affecting metabolic, inflammatory, and oxidative stress responses in several tissues through both genomic and nongenomic modes of action.

Minireview: Nuclear Hormone Receptor 4A Signaling: Implications for Metabolic Disease

Numerous members of the nuclear hormone receptor (NR) superfamily have been demonstrated to regulate metabolic function in a cell- and tissue-specific manner. This review brings together recent studies that have associated members of the NR superfamily, the orphan NR4A subgroup, with the regulation of metabolic function and disease. The orphan NR4A subgroup includes Nur77 (NR4A1), Nurr1 (NR4A2), and Nor-1 (NR4A3). Expression of these receptors is induced in multiple tissues by a diverse range of stimuli, including stimuli associated with metabolic function, such as: β-adrenoceptor agonists, cold, fatty acids, glucose, insulin, cholesterol, and thiazolidinediones. In vitro and in vivo gain- and loss-of-function studies in major metabolic tissues (including skeletal muscle, adipose, and liver cells and tissues) have associated the NR4A subgroup with specific aspects of lipid, carbohydrate, and energy homeostasis. Most excitingly, although these orphan receptors do not have known endogenous ligands, several small molecule agonists have recently been identified. The preliminary studies reviewed in this manuscript suggest that therapeutic exploitation of the NR4A subgroup may show utility against dyslipidemia, obesity, diabetes, and cardiovascular disease.

Secretin: Should we revisit its metabolic outcomes?

Metabolic pathologies such as Type 2 Diabetes have become a major health problem for worldwide populations. Unfortunately, efforts to cure and especially to prevent these significant global problems have so far been met with disappointment. Recently, the involvement of the gut-derived hormonal dysregulation in the development of obesity-related disturbances has been intensively studied. For instance, studies of gut-derived peptides such as peptide YY 3-36, glucagon-like peptide-1, oxyntomodulin and, more recently, ghrelin have significantly improved our understanding of mechanisms underlying weight and metabolic regulation. Even though early reports of the existence of secretin, the first peptide hormone to be described, date back as far as 1825, so much and yet so little is still known about its physiological role in mammals, including humans. However, recent years have provided a better understanding of how the release of secretin is regulated by enteral secretagogues. On the other hand, most basic questions about its role in the post-prandial regulation of metabolic functions in normal and pathophysiological conditions remain to be elucidated. The present work intends to review the physiology of secretin along with its central and peripheral outcomes on metabolic functions.

Adiponectin in health and diseases: from metabolic syndrome to tissue regeneration

Importance of the field: Adiponectin's importance as a regulator of metabolic functions has been assessed after observation of its downregulation in obese and diabetic patients. Decreased plasma adiponectin has been correlated with the onset of metabolic syndrome. Adiponectin has been proposed as an anti-inflammatory factor involved in protection of microvascular endothelium from inflammation insults.Areas covered in this review: The pleiotropic role of adiponectin in health and disease, with the double aim of describing the complex network of molecules engaged in its signaling in different tissues and underlining the gaps in the available data which need further investigation.What the reader will gain: Recent studies suggest that adiponectin can act as a paracrine/autocrine factor during tissue regeneration as it is a stem cell factor in hematopoiesis and vasculogenesis, as well as in bone, liver and muscle regeneration. This review underlines the new findings on adiponectin in tissue regeneration, particularly skeletal muscle regeneration.Take home message: The most recent findings suggest that adiponectin plays a role that goes beyond its well-known metabolic function. Indeed, this adipokine behaves as a stem factor for several tissues, giving a new perspective for its use as a tool for cell-based therapy of diseased/injured tissues.

Risperidone Treatment Increases CB1 Receptor Binding in Rat Brain

Background/Aims: Body weight gain is a common side effect of treatment with antipsychotics, but the mechanisms underlying this weight gain are unknown. Several factors may be involved in antipsychotic-induced body weight gain including the cannabinoid receptor 1 (CB₁), the serotonin receptor 2C, the ghrelin receptor, neuropeptide Y, adiponectin and proopiomelanocortin. We investigated whether the expression of these factors was affected in rats chronically treated with the antipsychotic risperidone. Methods: Male Sprague-Dawley rats were treated with risperidone (1.0 mg/kg/day) or vehicle (20% hydroxypropyl β-cyclodextrin) for 28 days. Expression of the aforementioned factors were examined together with plasma prolactin and ghrelin levels. Results: No difference in body weight gained during treatment was observed between risperidone and vehicle treated rats, but plasma risperidone levels positively correlated with visceral fat mass. Risperidone treatment increased CB₁ receptor binding in the arcuate nucleus (40%), hippocampus (25–30%) and amygdala (35%) without concurrent alterations in the CB₁ receptor mRNA. Risperidone treatment increased adiponectin mRNA. Conclusion: The present study showed that risperidone treatment altered CB₁ receptor binding in the rat brain. Risperidone-induced adiposity and metabolic dysfunction in the clinic may be explained by increased CB₁ receptor density in brain regions involved in appetite and regulation of metabolic function.