Maintenance Of Energy Homeostasis Research Articles

Activation of brown adipose tissue thermogenesis by electrical stimulation to the dorsal surface of the tissue in rats

Brown adipose tissue (BAT) is a heat-producing organ that plays an important role in maintenance of energy homeostasis. The purpose of this study was to test a novel method for stimulating BAT thermogenesis in rats. Application of electrical field stimulation to the dorsal surface of interscapular BAT caused a substantial rise in tissue temperature without affecting rectal temperature. The electrical stimulation failed to raise BAT temperature on the 2nd day after surgical sympathetic denervation. This is unlikely to be due to loss of thermogenic capacity, since neither UCP1 contents nor norepinephrine-induced thermogenesis were diminished 2 days after the denervation. A pharmacological experiment revealed that the BAT thermogenesis induced after electrical stimulation is mediated through β-adrenoceptors. The present study demonstrates that electrical stimulation applied to the dorsal surface of BAT is able to activate thermogenesis of BAT through mediation of norepinephrine released from sympathetic nerves. Our findings may provide a basis for developing a novel therapeutic procedure for obesity and related disorders.

Absence of RIP140 Reveals a Pathway Regulating glut4-Dependent Glucose Uptake in Oxidative Skeletal Muscle through UCP1-Mediated Activation of AMPK

Skeletal muscle constitutes the major site of glucose uptake leading to increased removal of glucose from the circulation in response to insulin. Type 2 diabetes and obesity are often associated with insulin resistance that can be counteracted by exercise or the use of drugs increasing the relative proportion of oxidative fibers. RIP140 is a transcriptional coregulator with a central role in metabolic tissues and we tested the effect of modulating its level of expression on muscle glucose and lipid metabolism in two mice models. Here, we show that although RIP140 protein is expressed at the same level in both oxidative and glycolytic muscles, it inhibits both fatty acid and glucose utilization in a fiber-type dependent manner. In RIP140-null mice, fatty acid utilization increases in the extensor digitorum longus and this is associated with elevated expression of genes implicated in fatty acid binding and transport. In the RIP140-null soleus, depletion of RIP140 leads to increased GLUT4 trafficking and glucose uptake with no change in Akt activity. AMPK phosphorylation/activity is inhibited in the soleus of RIP140 transgenic mice and increased in RIP140-null soleus. This is associated with increased UCP1 expression and mitochondrial uncoupling revealing the existence of a signaling pathway controlling insulin-independent glucose uptake in the soleus of RIP140-null mice. In conclusion, our findings reinforce the participation of RIP140 in the maintenance of energy homeostasis by acting as an inhibitor of energy production and particularly point to RIP140 as a promising therapeutic target in the treatment of insulin resistance.

Ghrelin – A Pleiotropic Hormone Secreted from Endocrine X/A-Like Cells of the Stomach

The gastric X/A-like endocrine cell receives growing attention due to its peptide products with ghrelin being the best characterized. This peptide hormone was identified a decade ago as a stimulator of food intake and to date remains the only known peripherally produced and centrally acting orexigenic hormone. In addition, subsequent studies identified numerous other functions of this peptide including the stimulation of gastrointestinal motility, the maintenance of energy homeostasis and an impact on reproduction. Moreover, ghrelin is also involved in the response to stress and assumed to play a role in coping functions and exert a modulatory action on immune pathways. Our knowledge on the regulation of ghrelin has markedly advanced during the past years by the identification of the ghrelin acylating enzyme, ghrelin-O-acyltransferase, and by the description of changes in expression, activation, and release under different metabolic as well as physically and psychically challenging conditions. However, our insight on regulatory processes of ghrelin at the cellular and subcellular levels is still very limited and warrants further investigation.

The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD +

The NAD(+)-dependent deacetylase SIRT1 is an evolutionarily conserved metabolic sensor of the Sirtuin family that mediates homeostatic responses to certain physiological stresses such as nutrient restriction. Previous reports have implicated fluctuations in intracellular NAD(+) concentrations as the principal regulator of SIRT1 activity. However, here we have identified a cAMP-induced phosphorylation of a highly conserved serine (S434) located in the SIRT1 catalytic domain that rapidly enhanced intrinsic deacetylase activity independently of changes in NAD(+) levels. Attenuation of SIRT1 expression or the use of a nonphosphorylatable SIRT1 mutant prevented cAMP-mediated stimulation of fatty acid oxidation and gene expression linked to this pathway. Overexpression of SIRT1 in mice significantly potentiated the increases in fatty acid oxidation and energy expenditure caused by either pharmacological β-adrenergic agonism or cold exposure. These studies support a mechanism of Sirtuin enzymatic control through the cAMP/PKA pathway with important implications for stress responses and maintenance of energy homeostasis.

Elevated plasma levels of adropin in heart failure patients

BackgroundRecent studies have suggested that a higher body mass index (BMI) is associated with an improved prognosis in heart failure (HF). Adropin is a recently identified protein that has been...

Effect of Manganese Chloride on the Neurochemical Profile of the Rat Hypothalamus

Manganese (Mn(2+))-enhanced magnetic resonance imaging studies of the neuronal pathways of the hypothalamus showed that information about the regulation of food intake and energy balance circulate through specific hypothalamic nuclei. The dehydration-induced anorexia (DIA) model demonstrated to be appropriate for studying the hypothalamus with Mn(2+)-enhanced magnetic resonance imaging. Manganese is involved in the normal functioning of a variety of physiological processes and is associated with enzymes contributing to neurotransmitter synthesis and metabolism. It also induces psychiatric and motor disturbances. The molecular mechanisms by which Mn(2+) produces alterations of the hypothalamic physiological processes are not well understood. (1)H-magnetic resonance spectroscopy measurements of the rodent hypothalamus are challenging due to the distant location of the hypothalamus resulting in limited measurement sensitivity. The present study proposed to investigate the effects of Mn(2+) on the neurochemical profile of the hypothalamus in normal, DIA, and overnight fasted female rats at 14.1 T. Results provide evidence that γ-aminobutyric acid has an essential role in the maintenance of energy homeostasis in the hypothalamus but is not condition specific. On the contrary, glutamine, glutamate, and taurine appear to respond more accurately to Mn(2+) exposure. An increase in glutamine levels could also be a characteristic response of the hypothalamus to DIA.

Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41)

The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.

Elevated Plasma Levels of Adropin in Heart Failure Patients

Recent studies have suggested that a higher body mass index (BMI) is associated with an improved prognosis in heart failure (HF). Adropin is a recently identified protein that has been implicated in the maintenance of energy homeostasis. In the present study, we investigated plasma adropin levels in patients with HF and evaluated the relationship between the levels and the severity of HF. The study group comprised 56 patients with HF and 20 control subjects, who were divided into 4 subgroups according to New York Heart Association (NYHA) functional classification. Plasma levels of adropin, brain natriuretic peptide (BNP) and cardiac hemodynamics were determined. Plasma adropin levels were significantly increased according to the severity of NYHA class in the patients with HF; control: 6.0 ± 0.3; NYHA functional Class II: 7.6 ± 0.4; NYHA functional Class III: 9.8 ± 0.5; NYHA functional Class IV: 12.4 ± 0.6 ng/mL (p<0.01). Similarly, plasma BNP levels were significantly increased in accordance with the NYHA class. Plasma adropin levels were correlated positively with BNP (r=0.723, p<0.001), interleukin-6 (IL-6) (r=0.326, p=0.007) and body mass index (BMI) (r=0.295, p=0.014), and negatively with left ventricular ejection fraction (LVEF) (r=-0.710, p<0.001). Plasma adropin levels were significantly increased according to the severity of HF, and BNP and BMI had independent impact on the plasma adropin level. These findings suggest that the augmented release of adropin may be involved in the pathogenesis of HF and further study is necessary to explain the precise role of adropin in HF.

Ablation of Sax2 gene expression prevents diet‐induced obesity

Regulation of energy homeostasis is mainly mediated by factors in the hypothalamus and the brainstem. Understanding these regulatory mechanisms is of great clinical relevance in the treatment of obesity and related diseases. The homeobox gene Sax2 is expressed predominantly in the brainstem, in the vicinity of serotonergic neurons, and in the ventral neural tube starting during early development. Previously, we have shown that the loss of function of the Sax2 gene in mouse causes growth retardation starting at birth and a high rate of postnatal lethality, as well as a dramatic metabolic phenotype. To further define the role of Sax2 in energy homeostasis, age-matched adult wild-type, Sax2 heterozygous and null mutant animals were exposed to a high-fat diet. Although food uptake among the different groups was comparable, Sax2 null mutants fed a high-fat diet exhibited a significantly lower weight gain compared to control animals. Unlike their counterparts, Sax2 null mutants did not develop insulin resistance and exhibited significantly lower leptin levels under both standard chow and high-fat diet conditions. Furthermore, neuropeptide Y, an important regulator of energy homeostasis, was significantly decreased in the forebrain of Sax2 null mutants on a high-fat diet. These data strongly suggest a critical role for Sax2 gene expression in diet-induced obesity. Sax2 gene expression may be required to allow the coordinated crosstalk of factors involved in the maintenance of energy homeostasis, possibly regulating the transcription of specific factors involved in energy balance.

Glucose regulates fatty acid binding protein interaction with lipids and peroxisome proliferator-activated receptor α

Although the pathophysiology of diabetes is characterized by elevated levels of glucose and long-chain fatty acids (LCFA), nuclear mechanisms linking glucose and LCFA metabolism are poorly understood. As the liver fatty acid binding protein (L-FABP) shuttles LCFA to the nucleus, where L-FABP directly interacts with peroxisome proliferator-activated receptor-α (PPARα), the effect of glucose on these processes was examined. In vitro studies showed that L-FABP strongly bound glucose and glucose-1-phosphate (K(d) = 103 ± 19 nM and K(d) = 20 ± 3 nM, respectively), resulting in altered L-FABP conformation, increased affinity for lipid ligands, and enhanced interaction with PPARα. In living cells, glucose stimulated cellular uptake and nuclear localization of a nonmetabolizable fluorescent fatty acid analog (BODIPY C-16), particularly in the presence of L-FABP. These data suggest for the first time a direct role of glucose in facilitating L-FABP-mediated uptake and distribution of lipidic ligands to the nucleus for regulation of PPARα transcriptional activity.

Adropin Is a Novel Regulator of Endothelial Function

Adropin is a recently identified protein that has been implicated in the maintenance of energy homeostasis and insulin resistance. Because vascular function and insulin sensitivity are closely related, we hypothesized that adropin may also exert direct effects on the endothelium. In vitro cell culture models were partnered with an in vivo murine injury model to determine the potential vascular effects of adropin. Adropin was expressed in human umbilical vein and coronary artery endothelial cells (ECs). Adropin-treated endothelial cells exhibited greater proliferation, migration and capillary-like tube formation and less permeability and tumor necrosis factor-α-induced apoptosis. In keeping with a vascular protective effect, adropin stimulated Akt Ser(473) and endothelial nitric oxide (NO) synthase Ser(1177) phosphorylation. The former was abrogated in the presence of the phosphatidylinositol 3-kinase inhibitor LY294002, whereas the latter was attenuated by LY294002 and by mitogen-activated protein kinase kinase 1 inhibition with PD98059. Together, these findings suggest that adropin regulates NO bioavailability and events via the phosphatidylinositol 3-kinase-Akt and extracellular signal regulated kinase 1/2 signaling pathways. Adropin markedly upregulated vascular endothelial growth factor receptor-2 (VEGFR2) transcript and protein levels, and in VEGFR2-silenced endothelial cells, adropin failed to induce phosphorylation of endothelial NO synthase, Akt, and extracellular signal regulated kinase 1/2, supporting VEGFR2 as an upstream target of adropin-mediated endothelial NO synthase activation. Last, adropin improved murine limb perfusion and elevated capillary density following induction of hindlimb ischemia. We report a potential endothelial protective role of adropin that is likely mediated via upregulation of endothelial NO synthase expression through the VEGFR2-phosphatidylinositol 3-kinase-Akt and VEGFR2-extracellular signal regulated kinase 1/2 pathways. Adropin represents a novel target to limit diseases characterized by endothelial dysfunction in addition to its favorable metabolic profile.

Roles of hormones in taste signaling.

Proper nutrition, avoidance of ingesting substances that are harmful to the whole organism, and maintenance of energy homeostasis are crucial for living organisms. Additionally, mammals possess a sophisticated system to control the types and content of food that we swallow. Gustation is a vital sensory skill for determining which food stuffs to ingest and which to avoid, and for maintaining metabolic homeostasis. It is becoming apparent that there is a strong link between metabolic control and flavor perception. Although the gustatory system critically influences food preference, food intake, and metabolic homeostasis, the mechanisms for modulating taste sensitivity by metabolic hormones are just now being explored. It is likely that hormones produced in the tongue influence the amounts and types of food that we eat: the hormones that we associate with appetite control, glucose homeostasis and satiety, such as glucagon-like peptide-1, cholecystokinin, and neuropeptide Y are also produced locally in taste buds. In this report, we will provide an overview of the peptidergic endocrine hormone factors that are present or are known to have effects within the gustatory system, and we will discuss their roles, where known, in taste signaling.

Enhanced Stat3 Activation in POMC Neurons Provokes Negative Feedback Inhibition of Leptin and InsulinSignaling in Obesity

Leptin-stimulated Stat3 activation in proopiomelanocortin (POMC)-expressing neurons of the hypothalamus plays an important role in maintenance of energy homeostasis. While Stat3 activation in POMC neurons is required for POMC expression, the role of elevated basal Stat3 activation as present in the development of obesity has not been directly addressed. Here, we have generated and characterized mice expressing a constitutively active version of Stat3 (Stat3-C) in POMC neurons (Stat3-C(POMC) mice). On normal chow diet, these animals develop obesity as a result of hyperphagia and decreased POMC expression accompanied by central leptin and insulin resistance. This unexpected finding coincides with POMC-cell-specific, Stat3-mediated upregulation of SOCS3 expression inhibiting both leptin and insulin signaling as insulin-stimulated PIP(3) (phosphatidylinositol-3,4,5 triphosphate) formation and protein kinase B (AKT) activation in POMC neurons as well as with the fact that insulin's ability to hyperpolarize POMC neurons is largely reduced in POMC cells of Stat3-C(POMC) mice. These data indicate that constitutive Stat3 activation is not sufficient to promote POMC expression but requires simultaneous PI3K (phosphoinositide 3-kinase)-dependent release of FOXO1 repression. In contrast, upon exposure to a high-fat diet, food intake and body weight were unaltered in Stat3-C(POMC) mice compared with control mice. Taken together, these experiments directly demonstrate that enhanced basal Stat3 activation in POMC neurons as present in control mice upon high-fat feeding contributes to the development of hypothalamic leptin and insulin resistance.

The 5′ adenosine monophosphate-activated protein kinase: Regulating the ebb and flow of cellular energetics

The 5′ adenosine monophosphate-activated protein kinase (AMPK) is a heterotrimeric, evolutionary conserved enzyme which has emerged as a critical regulator of skeletal muscle cellular bioenergetics. AMPK is activated by both chemical (adipokines) and mechanical (stretch, contraction) stimuli leading to metabolic changes within muscle cells that include increased fatty acid oxidation, glucose uptake and glycolysis, as well as the stimulation and regulation of mitochondrial biogenesis. Collectively these acute responses and chronic adaptations act to reduce cellular disturbances, resulting in tighter metabolic control and maintenance of energy homeostasis. This brief review will describe the structure, function and activation of AMPK in skeletal muscle and how this ubiquitous molecule may be a plausible target for the treatment of several lifestyle-related metabolic disorders.

GABA Keeps Up an Appetite for Life

In the arcuate nucleus of the hypothalamus, neurons that produce the neuropeptides NPY and AgRP play a vital role in the maintenance of energy homeostasis. In this issue, Wu et al. (2009) show that these neurons modulate feeding behavior in mice by providing GABAergic input to the parabrachial nucleus in the brainstem.

Antagonism of the mammalian target of rapamycin selectively mediates metabolic effects of epidermal growth factor receptor inhibition and protects human malignant glioma cells from hypoxia-induced cell death

Although inhibition of the epidermal growth factor receptor is a plausible therapy for malignant gliomas that, in vitro, enhances apoptosis, the results of clinical trials have been disappointing. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates starvation signals and generates adaptive responses that aim at the maintenance of energy homeostasis. Antagonism of mTOR has been suggested as a strategy to augment the efficacy of epidermal growth factor receptor inhibition by interfering with deregulated signalling cascades downstream of Akt. Here we compared effects of antagonism of mTOR utilizing rapamycin or a small hairpin RNA-mediated gene silencing to those of epidermal growth factor receptor inhibition or combined inhibition of epidermal growth factor receptor and mTOR in human malignant glioma cells. In contrast to epidermal growth factor receptor inhibition, mTOR antagonism neither induced cell death nor enhanced apoptosis induced by CD95 ligand or chemotherapeutic drugs. However, mTOR inhibition mimicked the hypoxia-protective effects of epidermal growth factor receptor inhibition by maintaining adenosine triphosphate levels. These in vitro experiments thus challenge the current view of mTOR as a downstream target of Akt that mediates antiapoptotic stimuli. Under the conditions of the tumour microenvironment, metabolic effects of inhibition of epidermal growth factor receptor, Akt and mTOR may adversely affect outcome by protecting the hypoxic tumour cell fraction.

Twist-1 Is a PPARδ-Inducible, Negative-Feedback Regulator of PGC-1α in Brown Fat Metabolism

Brown fat is specialized for energy expenditure, a process that is principally controlled by the transcriptional coactivator PGC-1alpha. Here, we describe a molecular network important for PGC-1alpha function and brown fat metabolism. We find that twist-1 is selectively expressed in adipose tissue, interacts with PGC-1alpha, and is recruited to the promoters of PGC-1alpha's target genes to suppress mitochondrial metabolism and uncoupling. In vivo, transgenic mice expressing twist-1 in the adipose tissue are prone to high-fat-diet-induced obesity, whereas twist-1 heterozygous knockout mice are obesity resistant. These phenotypes are attributed to their altered mitochondrial metabolism in the brown fat. Interestingly, the nuclear receptor PPARdelta not only mediates the actions of PGC-1alpha but also regulates twist-1 expression, suggesting a negative-feedback regulatory mechanism. These findings reveal an unexpected physiological role for twist-1 in the maintenance of energy homeostasis and have important implications for understanding metabolic control and metabolic diseases.

The Orexigenic Activity of the Hypothalamic Neuropeptide 26RFa Is Mediated by the Neuropeptide Y and Proopiomelanocortin Neurons of the Arcuate Nucleus

26RFa is a hypothalamic RFamide neuropeptide that was identified as the endogenous ligand of the orphan G protein-coupled receptor, GPR103, and that stimulates appetite in mice. Up until now, the mechanism of action of 26RFa in the hypothalamic control of food intake remains unknown. The high density of GPR103 in the arcuate nucleus (Arc) prompted us to investigate, in the present study, the effects of 26RFa on the rat neuropeptide Y (NPY)/proopiomelanocortin (POMC) system. Intracerebroventricular injection of 26RFa stimulated NPY expression and release in the basal hypothalamus, whereas it decreased POMC expression and alpha-MSH release, and these effects were associated with an increase in food intake. A double in situ hybridization procedure indicated that the 26RFa receptor is present in NPY neurons of the Arc, but not in POMC neurons. Central administration of NPY Y1 and Y5 receptor antagonists abolished the inhibitory effects of 26RFa on POMC expression and alpha-MSH release, and reversed 26RFa-induced food consumption. Finally, 26RFa antagonized the effects of leptin on NPY expression and release, POMC expression and alpha-MSH release, and food intake. Altogether, the present data demonstrate for the first time that 26RFa exerts its orexigenic activity by stimulating the release of NPY in the Arc, which in turn inhibits POMC neurons by activating the Y1 and Y5 receptors. It is also suggested that the balance 26RFa/leptin is an important parameter in the maintenance of energy homeostasis.

Characteristics of fat metabolism in skeletal muscle of rats after hypobaric hypoxic acclimation

Objective To investigate the characteristics of fat metabolism in rat skeletal muscle after hypobaric hypoxia acclimation. Methods Sprague-Dawley rats were divided into 3 groups randomly: control group (H0), hypoxic 5-day group (H5), and hypoxic 15-day group (H15). Animals of H5 and 15 groups were exposed to hypobaric hypoxia chamber simulating 5 000 m high altitude for 5 d or 15 d respectively, 23 h per day. H0 group stayed outside of chamber. The level of fatty acid oxidation and uptake, and glucose oxidation were examined, and the level of non-esterified fatty acids (NEFA), ATP and phosphocreatine (PCr) were also assayed in rat skeletal muscles. Results The contents of ATP and PCr in H5 group were lower than those in H0 and H15 groups ( P < 0.05), while there was no significant difference between H0 and H15. Compared with H0, the blood NEFA level in all hypoxia groups was increased significantly ( P < 0.05). The muscle NEFA level in H15 group was greatly higher than that in H0 and H5 groups. The rates of fatty acid oxidation and uptake in H15 group were significantly higher than those in H0 and H5 groups ( P < 0.05), and the rate of glucose oxidation in all hypoxia groups was significantly decreased than that in H0 group ( P < 0.05). Conclusion It is concluded that the enhanced fat oxidation may be one of the mechanisms in the maintenance of energy homeostasis after hypobaric hypoxic acclimation.

Integrated evaluation of the influence of a northern environment on human metabolism and physiological and psychoemotional states

A socially uniform group of apparently healthy people aged 30–59 years who live in cities of the European North (62°N) was examined. During the course of a year, blood metabolites, parameters of functioning of the cardiovascular system, the psychoemotional state, and actual nutrition were studied monthly. An optimal state of metabolism and physiological systems was found in May and December, whereas, during the winter-spring and autumn-winter periods, the maintenance of energy homeostasis was subjected to stress. Analysis of the data obtained helped to evaluate the key aspects in the adaptation of the body to seasonal changes in environmental factors: the role of anaerobic and aerobic oxidative processes in the maintenance of temperature homeostasis and the relationship between metabolic changes and cardiovascular system functioning and the psychoemotional state.