Regulation Of Energy Expenditure Research Articles

Glucagon Regulation of Energy Expenditure.

Glucagon’s ability to increase energy expenditure has been known for more than 60 years, yet the mechanisms underlining glucagon’s thermogenic effect still remain largely elusive. Over the last years, significant efforts were directed to unravel the physiological and cellular underpinnings of how glucagon regulates energy expenditure. In this review, we summarize the current knowledge on how glucagon regulates systems metabolism with a special emphasis on its acute and chronic thermogenic effects.

Prolactin-Releasing Peptide: Physiological and Pharmacological Properties.

Prolactin-releasing peptide (PrRP) belongs to the large RF-amide neuropeptide family with a conserved Arg-Phe-amide motif at the C-terminus. PrRP plays a main role in the regulation of food intake and energy expenditure. This review focuses not only on the physiological functions of PrRP, but also on its pharmacological properties and the actions of its G-protein coupled receptor, GPR10. Special attention is paid to structure-activity relationship studies on PrRP and its analogs as well as to their effect on different physiological functions, mainly their anorexigenic and neuroprotective features and the regulation of the cardiovascular system, pain, and stress. Additionally, the therapeutic potential of this peptide and its analogs is explored.

Cafestol increases fat oxidation and energy expenditure in Caenorhabditis elegans via DAF-12-dependent pathway

Cafestol, a coffee diterpene, is a known agonist of farnesoid X receptors (FXR), which are involved in cholesterol homeostasis. FXR plays critical roles in other lipid metabolic pathways, including fat oxidation; however, little is known about cafestol’s effects on fatty acid metabolism. Thus, the goal was to investigate cafestol’s effects on fatty acid metabolism using Caenorhabditis elegans. Cafestol at 60 µM reduced fat accumulation and increased locomotor activity (an indicator of energy expenditure) by 20% and 38%, respectively, compared to the control. Cafestol’s effects were dependent on daf-12 (a functional homolog of the human FXR) with upregulation of ech-1.1 (a homolog of enoyl-CoA hydratase involved in fatty acid β-oxidation) and tub-1 (an ortholog of the human TUBBY involved in the neurological regulation of energy expenditure) without any effects on lipogenesis, lipolysis or lipid uptake and transport. Therefore, cafestol increased fat oxidation and energy expenditure via DAF-12-dependent pathway in C. elegans.

Association of circulating exosomal miR-122 levels with BAT activity in healthy humans

Brown adipose tissue (BAT) plays an important role in body fat accumulation and the regulation of energy expenditure. Since the role of miRNAs in the pathogenesis of obesity and related metabolic diseases is contentious, we analyzed exosomal miRNAs in serum of healthy subjects with special references to BAT activity and body fat level. Forty male volunteers aged 20–30 years were recruited. Their BAT activity was assessed by fluorodeoxyglucose positron emission tomography and computed tomography after 2 h of cold exposure and expressed as a maximal standardized uptake value (SUVmax). Exosomal miRNA levels was analyzed using microarray and real-time PCR analyses. The miR-122-5p level in the high BAT activity group (SUV ≧ 3) was 53% lower than in the low BAT activity group (SUVmax <3). Pearson’s correlation analysis revealed that the serum miR-122-5p level correlated negatively with BAT activity and the serum HDL-cholesterol, and it correlated positively with age, BMI, body fat mass, and total cholesterol and triglyceride serum levels. Multivariate regression analysis revealed that BAT activity was associated with the serum miR-122-5p level independently of the other parameters. These results reveal the serum exosomal miR-122-5p level is negatively associated with BAT activity independently of obesity.

CIDEA Transcriptionally Regulates UCP1 for Britening and Thermogenesis in Human Fat Cells.

SummaryOur study identifies a transcriptional role of cell death-inducing DNA fragmentation factor-like effector A (CIDEA), a lipid-droplet-associated protein, whereby it regulates human adipocyte britening/beiging with consequences for the regulation of energy expenditure. The comprehensive transcriptome analysis revealed CIDEA's control over thermogenic function in brite/beige human adipocytes. In the absence of CIDEA, achieved by the modified dual-RNA-based CRISPR-Cas9nD10A system, adipocytes lost their britening capability, which was recovered upon CIDEA re-expression. Uncoupling protein 1 (UCP1), the most upregulated gene in brite human adipocytes, was suppressed in CIDEA knockout (KO) primary human adipocytes. Mechanistically, during induced britening, CIDEA shuttled from lipid droplets to the nucleus via an unusual nuclear bipartite signal in a concentration-dependent manner. In the nucleus, it specifically inhibited LXRα repression of UCP1 enhancer activity and strengthened PPARγ binding to UCP1 enhancer, hence driving UCP1 transcription. Overall, our study defines the role of CIDEA in increasing thermogenesis in human adipocytes.

Healthy diet is associated with gene expression in blood: the Framingham Heart Study

Genes in metabolic and nutrient signaling pathways play important roles in lifespan in model organisms and human longevity. The aim of this study was to examine the relation of a quantitative measure of healthy diet to gene expression in a community-based cohort. We used the 2015 Dietary Guidelines for Americans Adherence Index (DGAI) score to quantify key dietary recommendations of an overall healthy diet. Our current analyses included 2220 Offspring participants (mean age 66±9 y, 55.4% women) and 2941 Third-Generation participants (mean age 46±9 y, 54.5% women) from the Framingham Heart Study. Gene expression was profiled in blood through the use of the Affymetrix Human Exon 1.0 ST Array. We conducted a transcriptome-wide association study of DGAI adjusting for age, sex, smoking, cell counts, and technical covariates. We also constructed a combined gene score from genes significantly associated with DGAI. The DGAI was significantly associated with the expression of 19 genes (false discovery rate <0.05). The most significant gene, ARRDC3, is a member of the arrestin family of proteins, and evidence in animal models and human data suggests that this gene is a regulator of obesity and energy expenditure. The DGAI gene score was associated with body mass index (P=1.4×10-50), fasting glucose concentration (P=2.5×10-11), type 2 diabetes (P=1.1×10-5), and metabolic syndrome (P=1.8×10-32). Healthier diet was associated with genes involved in metabolic function. Further work is needed to replicate our findings and investigate the relation of a healthy diet to altered gene regulation.

Resting Energy Expenditure, Insulin Resistance and UCP1 Expression in Human Subcutaneous and Visceral Adipose Tissue of Patients With Obesity

Determinants of resting energy expenditure (REE) in humans are still under investigation, especially the association with insulin resistance. Brown adipose tissue (AT) regulates energy expenditure through the activity of the uncoupling protein 1 (UCP1). White AT browning is the process by which some adipocytes within AT depots acquire properties of brown adipocytes (“brite” adipocytes) and it correlates with metabolic improvement. We analyzed determinants of REE in patients with obesity and assessed UCP1 expression as a “brite” marker in abdominal subcutaneous AT (SAT) and visceral omental AT (VAT). Clinical data, REE, free fat mass (FFM), and fat mass (FM) were determined in 209 patients with obesity. UCP1, PPARG coactivator 1 alpha (PPARGC1A), transcription factor A, mitochondrial (TFAM), T-box transcription factor 1 (TBX1), and solute carrier family 27 member 1 (SLC27A1) expression was assayed in SAT and VAT samples, obtained during sleeve gastrectomy from 62 patients with obesity. REE and body composition data were also available for a subgroup of 35 of whom. In 209 patients with obesity a multiple regression model was computed with REE as the dependent variable and sex, waist, FFM, FM, homeostasis model assessment-insulin resistance (HOMA), interleukin-6 and High Density Lipoprotein-cholesterol as the independent variables. Only FFM, FM and HOMA were independently correlated with REE (r = 0.787, AdjRsqr = 0.602). In each patient VAT displayed a higher UCP1, PPARGC1A, TFAM, TBX1, and SLC27A1 expression than SAT and UCP1 expression in VAT (UCP1-VAT) correlated with Body Mass Index (BMI) (r = 0.287, p < 0.05). Introducing UCP1-VAT in the multivariate model, we showed that FFM, HOMA, interleukin-6, High Density Lipoprotein-cholesterol, and UCP1-VAT were independent factors correlated with REE (r = 0.736, AdjRsqr = 0.612). We confirmed that REE correlates with FFM, FM and HOMA in a large cohort of patients. Our results clearly showed that UCP1-VAT expression was significantly increased in severe human obesity (BMI > 50 kg/m2) and that it behaved as an independent predictor of REE. Lastly, we suggest that an increased REE and browning in metabolically complicated severe obesity could represent an effort to counteract further weight gain.

Regulation of energy expenditure and substrate oxidation by short-chain fatty acids.

Short-chain fatty acids (SCFAs) are metabolites produced from the fermentation of dietary fibre by the gut microbiota. High-fibre diets have been associated with lower weight gain and a number of reports have therefore investigated if these positive effects of a dietary fibre on body weight can be replicated through the direct administration of SCFAs. Many of these studies have reported that SCFAs can prevent or attenuate long-term body weight gain by increasing energy expenditure through increased lipid oxidation. The aim of the present review is to therefore evaluate the current evidence for an effect of SCFAs on whole-body energy expenditure and to assess the potential underlying mechanisms. The available data highlights that SCFAs can exert multiple effects at various organ and tissue sites that would cumulatively raise energy expenditure via a promotion of lipid oxidation. In conclusion, the present review proposes that dietary interventions and other therapies that augment gut-derived SCFAs and systemic availability may present an effective strategy to improve long-term energy balance and body weight management.

Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective.

The melanocortin-4 receptor (MC4R) can be endogenously activated by binding of melanocyte-stimulating hormones (MSH), which mediates anorexigenic effects. In contrast, the agouti-related peptide (AgRP) acts as an endogenous inverse agonist and suppresses ligand-independent basal signaling activity (orexigenic effects). Binding of ligands to MC4R leads to the activation of different G-protein subtypes or arrestin and concomitant signaling pathways. This receptor is a key protein in the hypothalamic regulation of food intake and energy expenditure and naturally-occurring inactivating MC4R variants are the most frequent cause of monogenic obesity. In general, obesity is a growing problem on a global scale and is of social, medical, and economic relevance. A significant goal is to develop optimized pharmacological tools targeting MC4R without adverse effects. To date, this has not been achieved because of inter alia non-selective ligands across the five functionally different MCR subtypes (MC1-5R). This motivates further investigation of (i) the three-dimensional MC4R structure, (ii) binding mechanisms of various ligands, and (iii) the molecular transfer process of signal transduction, with the aim of understanding how structural features are linked with functional-physiological aspects. Unfortunately, experimentally elucidated structural information is not yet available for the MC receptors, a group of class A G-protein coupled receptors (GPCRs). We, therefore, generated MC4R homology models and complexes with interacting partners to describe approximate structural properties associated with signaling mechanisms. In addition, molecular insights from pathogenic mutations were incorporated to discriminate more precisely their individual malfunction of the signal transfer mechanism.

Lipokines and Thermogenesis.

Adaptive thermogenesis is a catabolic process that consumes energy-storing molecules and expends that energy as heat in response to environmental changes. This process occurs primarily in brown and beige adipose tissue. Thermogenesis is regulated by many factors, including lipid derived paracrine and endocrine hormones called lipokines. Recently, technologic advances for identifying new lipid biomarkers of thermogenic activity have shed light on a diverse set of lipokines that act through different pathways to regulate energy expenditure. In this review, we highlight a few examples of lipokines that regulate thermogenesis. The biosynthesis, regulation, and effects of the thermogenic lipokines in several families are reviewed, including oloeylethanolamine, endocannabinoids, prostaglandin E2, and 12,13-diHOME. These thermogenic lipokines present potential therapeutic targets to combat states of excess energy storage, such as obesity and related metabolic disorders.

Regulation of Energy Expenditure by Brainstem GABA Neurons

Homeostatic control of core body temperature is essential for survival. Temperature is sensed by specific neurons, in turn eliciting both behavioral (i.e., locomotion) and physiologic (i.e., thermogenesis, vasodilatation) responses. Here, we report that a population of GABAergic (Vgat-expressing) neurons in the dorsolateral portion of the dorsal raphe nucleus (DRN), hereafter DRNVgat neurons, are activated by ambient heat and bidirectionally regulate energy expenditure through changes in both thermogenesis and locomotion. We find that DRNVgat neurons innervate brown fat via a descending projection to the raphe pallidus (RPa). These neurons also densely innervate ascending targets implicated in the central regulation of energy expenditure, including the hypothalamus and extended amygdala. Optogenetic stimulation of different projection targets reveals that DRNVgat neurons are capable of regulating thermogenesis through both a "direct" descending pathway through the RPa and multiple "indirect" ascending pathways. This work establishes a key regulatory role for DRNVgat neurons in controlling energy expenditure.

Tanycytes and the Control of Thyrotropin-Releasing Hormone Flux Into Portal Capillaries.

Central and peripheral mechanisms that modulate energy intake, partition and expenditure determine energy homeostasis. Thyroid hormones (TH) regulate energy expenditure through the control of basal metabolic rate and thermogenesis; they also modulate food intake. TH concentrations are regulated by the hypothalamus-pituitary-thyroid (HPT) axis, and by transport and metabolism in blood and target tissues. In mammals, hypophysiotropic thyrotropin-releasing hormone (TRH) neurons of the paraventricular nucleus of the hypothalamus integrate energy-related information. They project to the external zone of the median eminence (ME), a brain circumventricular organ rich in neuron terminal varicosities and buttons, tanycytes, other glial cells and capillaries. These capillary vessels form a portal system that links the base of the hypothalamus with the anterior pituitary. Tanycytes of the medio-basal hypothalamus express a repertoire of proteins involved in transport, sensing, and metabolism of TH; among them is type 2 deiodinase, a source of 3,3′,5-triiodo-L-thyronine necessary for negative feedback on TRH neurons. Tanycytes subtypes are distinguished by position and phenotype. The end-feet of β2-tanycytes intermingle with TRH varicosities and terminals in the external layer of the ME and terminate close to the ME capillaries. Besides type 2 deiodinase, β2-tanycytes express the TRH-degrading ectoenzyme (TRH-DE); this enzyme likely controls the amount of TRH entering portal vessels. TRH-DE is rapidly upregulated by TH, contributing to TH negative feedback on HPT axis. Alterations in energy balance also regulate the expression and activity of TRH-DE in the ME, making β2-tanycytes a hub for energy-related regulation of HPT axis activity. β2-tanycytes also express TRH-R1, which mediates positive effects of TRH on TRH-DE activity and the size of β2-tanycyte end-feet contacts with the basal lamina adjacent to ME capillaries. These end-feet associations with ME capillaries, and TRH-DE activity, appear to coordinately control HPT axis activity. Thus, down-stream of neuronal control of TRH release by action potentials arrival in the external layer of the median eminence, imbricated intercellular processes may coordinate the flux of TRH into the portal capillaries. In conclusion, β2-tanycytes appear as a critical cellular element for the somatic and post-secretory control of TRH flux into portal vessels, and HPT axis regulation in mammals.

Circulating Concentrations of GDF11 are Positively Associated with TSH Levels in Humans.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor (TGF)-β superfamily which declines with age and has been proposed as an anti-aging factor with regenerative effects in skeletal muscle in mice. However, recent data in humans and mice are conflicting, casting doubts about its true functional actions. The aim of the present study was to analyze the potential involvement of GFD11 in energy homeostasis in particular in relation with thyroid hormones. Serum concentrations of GDF11 were measured by enzyme-linked immunosorbent assay (ELISA) in 287 subjects. A highly significant positive correlation was found between GDF11 and thyroid-stimulating hormone (TSH) concentrations (r = 0.40, p < 0.001). Neither resting energy expenditure (REE) nor REE per unit of fat-free mass (REE/FFM) were significantly correlated (p > 0.05 for both) with GDF11 levels. In a multiple linear regression analysis, the model that best predicted logGDF11 included logTSH, leptin, body mass index (BMI), age, and C-reactive protein (logCRP). This model explained 37% of the total variability of logGDF11 concentrations (p < 0.001), with only logTSH being a significant predictor of logGDF11. After segregating subjects by TSH levels, those within the low TSH group exhibited significantly decreased (p < 0.05) GDF11 concentrations as compared to the normal TSH group or the high TSH group. A significant correlation of GDF11 levels with logCRP (r = 0.19, p = 0.025) was found. GDF11 levels were not related to the presence of hypertension or cardiopathy. In conclusion, our results show that circulating concentrations of GDF11 are closely associated with TSH concentrations and reduced in subjects with low TSH levels. However, GDF11 is not related to the regulation of energy expenditure. Our data also suggest that GDF11 may be involved in the regulation of inflammation, without relation to cardiac function. Further research is needed to elucidate the role of GDF11 in metabolism and its potential involvement in thyroid pathophysiology.

1897-P: Vertical Sleeve Gastrectomy Corrects the Metabolic Dysregulation Induced by Hepatocyte-Specific Ablation of p53 in Mice

p53 has been implicated in the pathogenesis of obesity and diabetes, in part, by regulating whole body energy homeostasis. Conflicting evidence from mice with global alterations in p53 expression suggests the effects of p53 on metabolism are tissue-specific. Despite the critical metabolic role of the hepatocyte, the role of hepatocyte p53 is undefined. Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes high rates of type 2 diabetes remission and improves energy homeostasis at the cellular level. To define the role of hepatocyte p53 in metabolic regulation and the impact of VSG in this context, we performed VSG or sham (S) surgery in high fat diet-fed male hepatocyte-specific p53 knockout (KO) and wild type (WT) mice (n=9-12). Sham-operated mice were fed ad libitum (S-AL) or food restricted to match their body weight to VSG-operated mice (S-WM). Body weight, food intake, adiposity, energy expenditure, and oral glucose tolerance were measured. Hepatocyte p53 ablation increased body weight which was corrected by food restriction and VSG (final weight (g): S-AL-WT=33±1, S-WM-WT=27±1, VSG-WT=29±1, S-AL-KO=38±1, S-WM-KO=28±1, VSG-KO=28±1, P&amp;lt;0.05). Hepatocyte p53 ablation decreased energy expenditure which was corrected by VSG but not by food restriction (EE (kcal/kg/min x 24hr): S-AL-WT=452±19, S-WM-WT=428±13, VSG-WT=527±37, S-AL-KO=396±10, S-WM-KO=422±10, VSG-KO=533±31, P&amp;lt;0.05). Hepatocyte p53 ablation impaired glucose homeostasis which was improved by food restriction and to a greater extent by VSG (glucose iAUC (mg/dl x 120min): S-AL-WT=17390±2736, S-WM-WT=16191±742, VSG-WT=8769±1214, S-AL-KO=21975±1841, S-WM-KO=14764±1190, VSG-KO=8832±867, P&amp;lt;0.05). These data reveal hepatocyte p53 is a key regulator of body weight and glucose homeostasis, largely through regulation of energy expenditure. VSG overcomes energetic impairments induced by hepatocyte p53 ablation by improving energy expenditure and glucose metabolism. Disclosure M.M. Holter: None. D. Garibay: None. A.K. McGavigan: None. L. Nguyen: None. E. Moore: None. E. Daugherity: None. P. Cohen: None. K.M. Kelly: None. R. Weiss: None. B. Cummings: None. Funding Cornell University; National Cancer Institute (R21CA195002)

1818-P: Brainstem GABAergic Circuits Regulating Energy Balance

Obesity is a serious disorder for which there is currently no effective treatment. The hypothalamus has long been studied as the critical node for regulating food intake and body weight; however, no effective targets have yet been identified within the hypothalamus for anti-obesity therapy. There is thus a critical, unmet need to identify other loci within the central nervous system that: a) potently regulate energy balance, through alterations in food intake and energy expenditure, and b) are potential therapeutic targets. We have recently found that the brainstem’s dorsal raphe nucleus (DRN) houses a small population of inhibitory, GABAergic neurons (hereafter DRNVgat neurons), which potently regulates energy balance, and concomitantly body weight. This is accomplished through the direct regulation of both food intake and energy expenditure, the latter component of which is achieved through both behavioral and physiologic mechanisms. However, the circuit mechanism(s) through which these neurons regulate energy homeostasis are poorly understood. In recent work, we made the unexpected finding that DRNVgat neurons project broadly throughout the brain to differentially regulate both food intake and energy expenditure. In particular, we have found that these neurons exhibit both ascending projections (to the bed nucleus of the stria terminalis, dorsomedial hypothalamus, and medial preoptic area), as well as descending projections to the raphe pallidus. This latter, descending projection forms part of a polysynaptic circuit anatomically linking DRNVgat neurons to brown fat. Using projection-specific optogenetic manipulations, we have found that these projections can all potently suppress thermogenesis, and differentially regulate food intake. Critically, these effects are scalable, with higher stimulation intensities leading to increasing effects on both feeding and thermogenesis. Together, this work uncovers a novel circuit mechanism through which DRNVgat neurons regulate energy balance. Disclosure A.R. Nectow: None. Funding American Diabetes Association/Pathway to Stop Diabetes (1-18-ACE-49, 1-18-IBS-148 to A.R.N.); Foundation for Prader-Willi Research; National Alliance for Research on Schizophrenia and Depression

1853-P: Transforming Growth Factor Beta 1 Acts as a Hepatokine in Control of Glucose and Energy Metabolism

Liver and adipose tissue are crucial for blood glucose and energy homeostasis, while impaired regulation of hepatic glucose production (HGP) and energy expenditure contribute to hyperglycemia and excessive fat storage in type 2 diabetes mellitus. Hepatokines are proteins secreted by hepatocytes, and several hepatokines have been shown to directly affect glucose and energy expenditure. In this study, we investigated the role of transforming growth factor beta 1 (TGF-β1) in hepatocytes in regulating glucose and energy homeostasis. We generated the liver-specific TGF-β1 knockout mice and found that the mice exhibited lower blood glucose, increased hepatic insulin sensitivity compared with wild type (WT) control mice. Using the mouse primary hepatocytes, we found that TGF-β1 deletion impaired HGP and TGF-β1 treatment promoted protein kinase A (PKA) signaling and stimulated the nuclear translocation of FoxO1. Under high fat diet (HFD) treatment, hepatic TGF-β1 deficiency protected mice from HFD-induced obesity and insulin resistance, decreased HGP and improved energy expenditure. Moreover, we used hepatic insulin receptor substrate-1, 2 (IRS1, 2) knockout (DKO) mice and deleted the TGF-β1 gene in the liver of DKO mice. We found that hepatic TGF-β1 ablation prevented hyperglycemia and hyperinsulinemia in DKO mice. Deletion of TGF-β1 or neutralization of TGF-β1 with antibody significantly decreased HGP of DKO hepatocytes. Additionally, hepatic TGF-β1 ablation enhanced thermogenesis and inguinal white adipose tissue (iWAT) browning in DKO mice. These findings underscore an important role of hepatic TGF-β1 in contribution to systemic glucose and energy homeostasis. Thus, hepatic TGF-β1 may serve as a therapeutic target for control of glucose and energy homeostasis in insulin resistance and type 2 diabetes mellitus. Disclosure Q. Pan: None. Y. Chen: None. D. Kim: None. Z. Shen: None. W. Yang: None. X. Li: None. Y. Sun: None. S. Guo: None. Funding American Diabetes Association (1-15-CD-09 to S.G.)

Cafestol Increases Fat Oxidation and Energy Expenditure in Caenorhabditis Elegans via DAF-12-dependent Pathway (OR34-02-19)

ObjectivesCafestol, a diterpene found in coffee beans, is reported to be an agonist of farnesoid X receptors (FXR), nuclear hormone receptors involved in cholesterol homeostasis. It is also known that FXR plays critical roles in other metabolic pathways, including lipid metabolism; however, little is known about cafestol’s effects on lipid metabolism. The goal of the current study was to investigate the effects of cafestol on lipid metabolism using Caenorhabditis elegans as a model system. MethodsC. elegans was treated for 2 days with cafestol or 0.2% dimethyl sulfoxide (vehicle control). Triglycerides, locomotor behavior (an indicator of energy expenditure) and lipid metabolism-related gene expressions were measured. ResultsCafestol at 60 μM significantly reduced fat accumulation by 20% compared to the control. Cafestol increased locomotor activity by 38% compared to the control. The effects of cafestol on fat accumulation were dependent on daf-12 (a functional homolog of the human FXR) and further confirmed by the upregulation of a DAF-12-target gene, fard-1 (the homolog of the human fatty acid reductase 1). Cafestol’s fat-lowering effects were also dependent on tub-1 (an ortholog of the human TUBBY), which is involved in the neurological regulation of energy expenditure. Cafestol upregulated the expression of ech-1.1, involved in fatty acid β-oxidation; however, no effects of cafestol were observed on lipogenesis, lipolysis or lipid uptake and transport. ConclusionsIn conclusion, cafestol regulates lipid metabolism in C. elegans by increasing fatty acid β-oxidation and energy expenditure dependent on daf-12/FXR. Funding SourcesBrazilian National Counsel of Technological and Scientific Development (CNPq).

Central, but not systemic, thermoregulatory effects of leptin are impaired in rats with obesity: interactions with GABAB agonist and antagonist.

Leptin is an adipokine that regulates body weight by decreasing appetite and increasing energy expenditure. Besides the effects on food intake, leptin can regulate energy expenditure at least in part by modulating thermogenesis. Many of the effects of leptin are attributable to action in the central nervous system, particularly in the hypothalamus. Common forms of obesity are associated with increased leptin levels and a failure to suppress feeding and mediate weight loss in response to exogenous leptin. This apparent leptin ineffectiveness defines a state of so-called leptin resistance. We examined the effect of leptin on core body temperature in rats with normal weight and diet-induced obesity (DIO), as well as thermoregulatory interactions between leptin and GABAB-agonist and an antagonist. We found that leptin retains the ability to induce hyperthermic effect in rats with DIO. Additionally, temperature responses produced by GABAB agonist and antagonist are altered in a state of obesity and by administration of leptin. We evaluated whether the medial preoptic area of the anterior hypothalamus (MPA) still remains sensitive to leptin action during DIO. Using extracellular recordings of neurons and phospho-signal transducer and the activator of transcription 3 (pSTAT3) immunohistochemistry, we have provided strong evidence that leptin signaling in the MPA is impaired in obese rats. We believe that leptin resistance in the MPA may play a role in the pathogenesis of obesity and obesity-related disease states.

Gastric Leptin and Tumorigenesis: Beyond Obesity

Leptin, an adipocyte-derived hormone and its receptor (ObR) expressed in the hypothalamus are well known as an essential regulator of appetite and energy expenditure. Obesity induces abundant leptin production, however, reduced sensitivity to leptin leads to the development of metabolic disorders, so called leptin resistance. The stomach has been identified as an organ that simultaneously expresses leptin and ObR. Accumulating evidence has shown gastric leptin to perform diverse functions, such as those in nutrient absorption and carcinogenesis in the gastrointestinal system, independent of its well-known role in appetite regulation and obesity. Overexpression of leptin and phosphorylated ObR is implicated in gastric cancer in humans and in murine model, and diet-induced obesity causes precancerous lesions in the stomach in mice. While the underlying pathomechanisms remain unclear, leptin signaling can affect gastric mucosal milieu. In this review, we focus on the significant role of the gastric leptin signaling in neoplasia and tumorigenesis in stomach in the context of hereditary and diet-induced obesity.

Machine Learning Based Classification of Resting-State fMRI Features Exemplified by Metabolic State (Hunger/Satiety).

ObjectiveResting-state functional magnetic resonance imaging (rs-fMRI) has become an essential measure to investigate the human brain’s spontaneous activity and intrinsic functional connectivity. Several studies including our own previous work have shown that the brain controls the regulation of energy expenditure and food intake behavior. Accordingly, we expected different metabolic states to influence connectivity and activity patterns in neuronal networks.MethodsThe influence of hunger and satiety on rs-fMRI was investigated using three connectivity models (local connectivity, global connectivity and amplitude rs-fMRI signals). After extracting the connectivity parameters of 90 brain regions for each model, we used sequential forward floating selection strategy in conjunction with a linear support vector machine classifier and permutation tests to reveal which connectivity model differentiates best between metabolic states (hunger vs. satiety).ResultsWe found that the amplitude of rs-fMRI signals is slightly more precise than local and global connectivity models in order to detect resting brain changes during hunger and satiety with a classification accuracy of 81%.ConclusionThe amplitude of rs-fMRI signals serves as a suitable basis for machine learning based classification of brain activity. This opens up the possibility to apply this combination of algorithms to similar research questions, such as the characterization of brain states (e.g., sleep stages) or disease conditions (e.g., Alzheimer’s disease, minimal cognitive impairment).