White Adipose Research Articles

Ginger Water Reduces Body Weight Gain and Improves Energy Expenditure in Rats.

Obesity is a serious global problem that causes predisposition to numerous serious diseases. The current study aims to investigate the effect of ginger water on body weight and energy expenditure through modulation of mRNA expression of carbohydrate and lipid metabolism. A white colored liquid obtained during freeze-drying of fresh rhizomes of Zingiber officinal was collected and named ginger water. It was used to treat rats, then blood and tissue samples were collected from the liver and white adipose at the end of the experiment. The serum was prepared and used for biochemical assays, while tissue samples were used for RNA isolation and gene expression analysis via Reverse transcription polymerase chain reaction (RT-PCR). Results of High Performance Liquid Chromatography (HPLC) analysis of ginger water revealed the presence of chrysin and galangin at concentrations of 0.24 µg/mL and 0.53 µg/mL, respectively. Average body weight gain decreased significantly in groups that received ginger water. In addition, both total cholesterol and serum triacylglycerol were reduced in the groups that received ginger water. Furthermore, mRNA expression of Sterol regulatory element-binding protein 1 (SREBP-1c) in the liver and leptin in adipose tissues were downregulated, while those of adiponectin, hepatic carnitine palmitoyltransferase1 (CPT-1), acyl-coA oxidase (ACO), Glucose transporter 2 (GLUT-2), and pyruvate kinase (PK) were upregulated in ginger water-treated groups. These results clearly revealed the lowering body weight gain effect of ginger water, which most likely occurs at the transcriptional level of energy metabolizing proteins.

Enzymatic preparation of a low-molecular-weight polysaccharide rich in uronic acid from the seaweed Laminaria japonica and evaluation of its hypolipidemic effect in mice.

Here, we describe a method combining thermo-acid pretreatment and alginate lyase hydrolysis to prepare a low-molecular-weight polysaccharide from the seaweed Laminaria japonica (SP). The in vitro results showed that SP displayed obvious absorption of oil (2.95 g g-1) and cholesterol (21.87 g g-1 at pH 2.0). In addition, the in vivo assessment of SP-related anti-obesity effects in C57BL/6J mice fed a high-fat diet and treated with SP for 8 weeks revealed that SP significantly reduced weight gain and lipid accumulation in white adipose and liver tissues, improved serum lipid profiles, and ameliorated intestinal damage. Moreover, SP activated the AMP-activated protein kinase pathway in liver tissues, downregulated sterol regulatory element-binding protein and fatty acid synthase, and suppressed lipid synthesis. These findings indicated that SP extracted from L. japonica might represent a potent functional food exhibiting anti-obesity effects.

Structural attributes influencing unbound tissue distribution

Unbound tissue-to-plasma partition coefficients (Kpuu) were determined for 56 structurally diverse compounds in rats following intravenous infusion. Five tissues were included in the study: white adipose, brain, heart, liver, and skeletal muscle. The rank ordering of the median tissue Kpuu values was: liver (4.5) > heart (1.8) > adipose (1.2) > skeletal muscle (0.6) > brain (0.05), with liver being most enriched and brain most impaired. The median Kpuu values of acids and zwitterions were lower than those of bases and neutrals in all tissues but liver. Selective tissue distribution was observed, dependent upon chemotype, which demonstrated the feasibility of targeting or restricting drug exposure in certain tissues through rational design. Physicochemical attributes for Kpuu were identified using recursive partitioning, which further classified compounds with enriched or impaired tissue distribution. The attributes identified provided valuable insight on design principles for asymmetric tissue distribution to improve efficacy or reduce toxicity.

Characterization of Lipid Profiles after Dietary Intake of Polyunsaturated Fatty Acids Using Integrated Untargeted and Targeted Lipidomics.

Illuminating the comprehensive lipid profiles after dietary supplementation of polyunsaturated fatty acids (PUFAs) is crucial to revealing the tissue distribution of PUFAs in living organisms, as well as to providing novel insights into lipid metabolism. Here, we performed lipidomic analyses on mouse plasma and nine tissues, including the liver, kidney, brain, white adipose, heart, lung, small intestine, skeletal muscle, and spleen, with the dietary intake conditions of arachidonic acid (ARA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) as the ethyl ester form. We incorporated targeted and untargeted approaches for profiling oxylipins and complex lipids such as glycerol (phospho) lipids, sphingolipids, and sterols, respectively, which led to the characterization of 1026 lipid molecules from the mouse tissues. The lipidomic analysis indicated that the intake of PUFAs strongly impacted the lipid profiles of metabolic organs such as the liver and kidney, while causing less impact on the brain. Moreover, we revealed a unique lipid modulation in most tissues, where phospholipids containing linoleic acid were significantly decreased in mice on the ARA-supplemented diet, and bis(monoacylglycero)phosphate (BMP) selectively incorporated DHA over ARA and EPA. We comprehensively studied the lipid profiles after dietary intake of PUFAs, which gives insight into lipid metabolism and nutrition research on PUFA supplementation.

Plasmodium Infection Induces Dyslipidemia and a Hepatic Lipogenic State in the Host through the Inhibition of the AMPK-ACC Pathway

Malaria is a major parasitic disease of humans and is a health public problem that affects more than 100 countries. In 2017, it caused nearly half a million deaths out of 219 million infections. Malaria is caused by the protozoan parasites of the genus Plasmodium and is transmitted by female mosquitoes of the genus Anopheles. Once in the bloodstream, Plasmodium merozoites invade erythrocytes and proliferate until the cells lyses and release new parasites that invade other erythrocytes. Remarkably, they can manipulate the vertebrate host’s lipid metabolism pathways, since they cannot synthesize lipid classes that are essential for their development and replication. In this study, we show that mice infected with Plasmodium chabaudi present a completely different plasma profile from control mice, with marked hyperproteinemia, hypertriglyceridemia, hypoglycemia, and hypocholesterolemia. In addition, white adipose and hepatic tissue and analyses from infected animals revealed the accumulation of triacylglycerol in both tissues and free fatty acids and free cholesterol in the liver. Hepatic mRNA and protein expression of key enzymes and transcription factors involved in lipid metabolism were also altered by P. chabaudi infection, leading to a lipogenic state. The enzyme 5′ AMP-activated protein kinase (AMPK), a master regulator of cell energetic metabolism, was also modulated by the parasite, which reduced AMPK phosphorylation levels upon infection. Pretreatment with metformin for 21 days followed by infection with P. chabaudi was effective in preventing infection of mice and also lowered the hepatic accumulation of lipids while activating AMPK. Together, these results provide new and important information on the specific molecular mechanisms induced by the malaria parasite to regulate hepatic lipid metabolism in order to facilitate its development, proliferation, and lifespan in its vertebrate host.

Brown Adipose Tissue Remodeling Precedes Cardiometabolic Abnormalities Independent of Overweight in Fructose-Fed Mice

Background: Body fat distribution is a risk factor for several health conditions, although the literature shows that excess body fat is not always associated with cardiometabolic abnormalities in all subjects.Objectives: To investigate glucose, lipid, and hepatic metabolism, along with white (WAT) and brown adipose tissue (BAT) remodeling in a mice model of short-term fructose feeding.Methods: Male C57BL/6 mice (n = 10-11/group) were fed for four weeks with control diet (AIN93-M) or experimental diets rich in glucose or fructose. We investigated body weight, body adiposity, blood glucose, lipid and hepatic parameters, and WAT and BAT histopathology.Results: Fructose feeding did not promote either weight gain or adipocyte hypertrophy of visceral and subcutaneous WAT depots, but the fat was redistributed toward visceral depots. Fructose-fed mice did not show glucose, lipid, and hepatic metabolic dysfunction, except for an elevation in total cholesterol and hepatic weight. BAT mass did not increase, and it was proportionally reduced compared with visceral WAT in fructose feed mice. BAT suffered early adverse morphological remodeling, characterized by increased lipid deposition and enlargement of intracellular lipid droplets.Conclusion: Short-term fructose feeding redistributes fat among WAT depots, alters the ratio between BAT andvisceral WAT, and promotes BAT adverse remodeling, characterized by enlarged intracellular lipid droplets.

Acute and chronic responses to exercise training-induced irisin in browning of white fat

Nowadays, is well established that the benefits induced by exercise training (ET) affects not only skeletal muscle, but also other non-contractile organs over time. One potential mechanism underlying this crosstalk is the synthesis and secretion of several biological active factors, such as irisin, by muscle contractile activity. This hormone has been described to be able to induce a brown adipocyte-like phenotype in white adipose (WAT), increase whole-body metabolic rate, and therefore prevent and/or treat obesity-related metabolic diseases. Thus, the modulatory impact of ET on WAT may also occur through skeletal muscle - adipose organ axis. In this review, we summarize the acute and chronic adaptations to ET-induced irisin synthesis and secretion on the development of browning of white fat and, thus, providing an overview of the potential preventive and therapeutic role of ET on the obesity-related underlying pathways.

Convergent neuronal projections from paraventricular nucleus, parabrachial nucleus, and brainstem onto gastrocnemius muscle, white and brown adipose tissue in male rats.

When energy balance is altered by aerobic exercise, starvation, and cold exposure, for example, there appears to be coordination of the responses of skeletal muscle, white adipose (WAT), and brown adipose (BAT) tissues. We hypothesized that WAT, BAT, and skeletal muscle may share an integrated regulation by the central nervous system (CNS); specifically, that neurons in brain regions associated with energy balance would possess neuroanatomical connections to permit coordination of multiple, complementary responses in these downstream tissues. To study this, we used trans-neuronal viral retrograde tract tracing, using isogenic strains of pseudorabies virus (PRV) with distinct fluorescent reporters (either eGFP or mRFP), injected pairwise into male rat gastrocnemius, subcutaneous WAT and interscapular BAT, coupled with neurochemical characterization of specific cell populations for cocaine- and amphetamine-related transcript (CART), oxytocin (OX), corticotrophin releasing hormone (CRH) and calcitonin gene-related peptide (CGRP). Cells in the paraventricular (PVN) and parabrachial (PBN) nuclei and brainstem showed dual projections to muscle + WAT, muscle + BAT, and WAT + BAT. Dual PRV-labeled cells were found in parvocellular, magnocellular and descending/pre-autonomic regions of the PVN, and multiple structural divisions of the PBN and brainstem. In most PBN subdivisions, more than 50% of CGRP cells dually projected to muscle + WAT and muscle + BAT. Similarly, 31-68% of CGRP cells projected both to WAT + BAT. However, dual PRV-labeled cells in PVN only occasionally expressed OX or CRH but not CART. These studies reveal for the first time both separate and shared outflow circuitries among skeletal muscle and subcutaneous WAT and BAT.

Strategies and methods for the correction of obesity and associated cardiovascular risk

Today, there is a need to study obesity from the perspective of associated with it cardiovascular risk correcting. Future researches will have to study the pathophysiology of adipose tissue in greater detail, including tissue, cellular and molecular levels, in order to develop the most effective strategies for therapeutic and preventive measures. At the same time, taking into account the basic ideas about the role of cardiorespiratory fitness in the etiopathogenesis of cardiovascular diseases, the ratio of fat free and fat mass, white and brown adipose tissue, subcutaneous fat and visceral adipose tissue, main directions of these measures becomes obvious. This article discusses strategies for correcting obesity and associated cardiovascular risk as part of primary and secondary prevention of cardiovascular diseases and suggests an algorithm for developing an individual program of preventive measures for an obese patient.

SUN-LB019 Myeloid Krüppel-like Factor 2 is a Critical Regulator of Metabolic Inflammation

Substantial evidence implicates crosstalk between metabolic tissues and the immune system, both centrally and peripherally, in the inception and progression of obesity. Nodal factors that orchestrate systemic “metaflammation” remain very incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. Macrophages with KLF2 deletion enrich transcriptional networks associated with metabolic syndrome. In mice and humans, consumption of a fatty diet is associated with downregulation of KLF2 in myeloid cells. Mice with myeloid specific deletion of KLF2 (K2KO) exhibited basal metabolic disturbances including increased feeding contributing to rapid weight gain. Stimulating K2KO mice with metaflammatory stress (high fat diet) caused genotype-dependent increases in insulin resistance and non-alcoholic steatohepatitis. Mechanistically, loss of myeloid KLF2 increased metaflammation in peripheral (white adipose, liver) and central (hypothalamus) metabolic tissues, demonstrating the widespread regulation that KLF2 poses on metabolic homeostasis. This regulation occurs, in part, through KLF2’s attenuation of inflammasome activation, a major pathogenic mechanism of metabolic disease. Critically, overexpression of KLF2 in the myeloid compartment protected mice from long-term HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a decisive regulator of central and peripheral metabolic inflammation in homeostasis and disease. Funding: This work was funded by the American Heart Association and National Institutes of Health from the NHLBI and NIGMS. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Multi-Level Comparative Framework Based on Gene Pair-Wise Expression Across Three Insulin Target Tissues for Type 2 Diabetes.

Type 2 diabetes (T2D) is known as a disease caused by gene alterations characterized by insulin resistance, thus the insulin-responsive tissues are of great interest for T2D study. It’s of great relevance to systematically investigate commonalities and specificities of T2D among those tissues. Here we establish a multi-level comparative framework across three insulin target tissues (white adipose, skeletal muscle, and liver) to provide a better understanding of T2D. Starting from the ranks of gene expression, we constructed the ‘disease network’ through detecting diverse interactions to provide a well-characterization for disease affected tissues. Then, we applied random walk with restart algorithm to the disease network to prioritize its nodes and edges according to their association with T2D. Finally, we identified a merged core module by combining the clustering coefficient and Jaccard index, which can provide elaborate and visible illumination of the common and specific features for different tissues at network level. Taken together, our network-, gene-, and module-level characterization across different tissues of T2D hold the promise to provide a broader and deeper understanding for T2D mechanism.

Impact of Estrogens on the Regulation of White, Beige, and Brown Adipose Tissue Depots.

As adipose tissue depots are active endocrine organs, they secrete a variety of hormones (including estrogens from white adipose) and inflammatory mediators, which have important implications in numerous obesity-associated diseases. Adipose tissues are broadly characterized as consisting of white, beige, and brown depot types. The endocrine, metabolic, and inflammatory profiles of adipose are depot dependent and influenced by the estrogenic and androgenic status of the adipose tissue. Estrogen receptors mediate both the genomic and nongenomic actions of estrogens and are expressed in the brain, heart, and other peripheral tissues. All three known estrogen receptor α (ERα) and estrogen receptor β (ERβ), and the G-protein coupled estrogen receptor (GPER/GPR30) are expressed in white adipose and can modulate adipose mass. Expression of each receptor is dependent on depot location, adipose cell type, and estrogen levels. Estrogen receptor expression profiles in beige and brown adipocytes are less well established. This review will discuss the effects of estrogens on the differential deposition of the major adipose tissues and the impact of estrogens within white adipose depots. © 2019 American Physiological Society. Compr Physiol 9:457-475, 2019.

PO-028 Advances in Research on Exercise-Mediated miRNAs Regulating White Fat Browning

Objective In this paper, we reviewed the positive and negative regulation of miRNAs on white fat browning and the effects of exercise on miRNAs and white fat browning, and explored the mechanism and physiological significance of miRNAs on white fat browning, and prospecting white fat browning. Prospects provide experimental researchers with new research ideas and provide potential methods for the prevention and treatment of obesity and metabolic related diseases.
 Methods Through the literature data method, 110 articles were reviewed. Finally, 75 papers (including 69 English papers) were used to analyze the research progress of exercise-mediated miRNAs regulating white fat browning, and provide new models for experimenters. Research ideas.
 Results The analysis found that only a small number of miRNAs have a mechanism of action on white fat browning. In the future, the mechanism of action of other miRNAs on white fat browning should be further studied. The research on the effects of exercise on miRNAs is still in its infancy. There are few studies on the effects of exercise on white fat browning, and there is controversy. In the future, it is necessary to clarify the effects of different exercise modes on the regulation of white fat browning by miRNAs. Mechanism and physiological significance.In summary, miRNAs are closely related to the process of white fat browning, miRNAs can regulate the transcription of brown genes, and miRNAs have positive and negative regulation of white fat browning. However, the mechanism of action of only a small number of miRNAs on white fat browning has been elucidated (as shown in Figure 1), and the mechanism of action of other miRNAs on white fat browning should be further studied in the future. It is worth noting that the current studies on the browning of white fat by miRNAs have only been verified in animal experiments and human cell culture, and the exact mechanism of action in humans remains to be further verified. In terms of disease, RNA-based therapy has entered clinical trials, and further exploration of the function of miRNAs in white and brown adipose tissue will be a new treatment to help humans treat obesity and its subsequent complications. In addition, research on the effects of exercise on miRNAs is still in its infancy. There are few studies on the effects of exercise on browning of white fat, and there is controversy. In the future, it is necessary to clarify more different ways to induce miRNAs to regulate white fat browning. The mechanism of action and physiological significance make the research system in this field more perfect, and find as many miRNAs as possible to effectively intervene in obesity, promote brown fat production and white fat browning, and prevent and treat human obesity and metabolic abnormal diseases.
 Conclusions In summary, miRNAs are closely related to the process of white fat browning, miRNAs can regulate the transcription of brown genes, and miRNAs have positive and negative regulation of white fat browning. However, the mechanism of action of only a small number of miRNAs on white fat browning has been elucidated (as shown in Figure 1), and the mechanism of action of other miRNAs on white fat browning should be further studied in the future. It is worth noting that the current studies on the browning of white fat by miRNAs have only been verified in animal experiments and human cell culture, and the exact mechanism of action in humans remains to be further verified. In terms of disease, RNA-based therapy has entered clinical trials, and further exploration of the function of miRNAs in white and brown adipose tissue will be a new treatment to help humans treat obesity and its subsequent complications. In addition, research on the effects of exercise on miRNAs is still in its infancy. There are few studies on the effects of exercise on browning of white fat, and there is controversy. In the future, it is necessary to clarify more different ways to induce miRNAs to regulate white fat browning. The mechanism of action and physiological significance make the research system in this field more perfect, and find as many miRNAs as possible to effectively intervene in obesity, promote brown fat production and white fat browning, and prevent and treat human obesity and metabolic abnormal diseases.

High-fat diet affects pregestational adiposity and glucose tolerance perturbing gestational placental macronutrient transporters culminating in an obese offspring in wild-type and glucose transporter isoform 3 heterozygous null mice

We examined the effect of a high-fat diet (HFD) vs. control diet (CD) upon pregestational and gestational wild-type (wt) and glucose transporter (glut)3 heterozygous (glut3+/−) female mice and observed an increase in pregestational body weights, white adiposity (wt > glut3+/−), circulating cholesterol, and high-density lipoproteins, with glucose intolerance in both genotypes. The HFD-exposed offspring displayed reduced birth weight with catch up to CD-fed in wt vs. an increased birth weight persisting as such at weaning by day 21 in glut3+/− mice. To decipher the mechanism behind this genotype-specific difference in the HFD offspring's phenotype, we first examined placental macronutrient transporters and noted HFD-induced increase in CD36 in wt with no change in other FATPs, sodium-coupled neutral amino acid transporters and system L amino acid transporter in both genotypes. In contrast, while placental Glut1 increased in both the genotypes, only Glut3 increased in the glut3+/− genotype in response to HFD. Hence, we next assessed glut3+/− embryonic (ES) cells under differing stressors of low glucose, hypoxia and inhibition of oxidative phosphorylation. Reduced Glut3-mediated glucose uptake in glut3+/− vs. wt ES cells culminated in deficient growth. We conclude that maternal HFD affects the in utero growth potential of the offspring by altering placental CD36 and Glut1 concentrations. In contrast, a differential effect on placental Glut3 concentrations between glut3+/− and wt genotypes is evident, with an increase occurring in the glut3+/− genotype alone. Deficient Glut3 in ES cells interferes with glucose uptake, cell survival and growth being further exaggerated with low glucose, hypoxia and inhibition of oxidative phosphorylation.

Conserved transcriptional activity and ligand responsiveness of avian PPARs: Potential role in regulating lipid metabolism in mirgratory birds

Migratory birds undergo metabolic remodeling in tissues, including increased lipid storage in white adipose and fatty acid uptake and oxidation in skeletal muscle, to optimize energy substrate availability and utilization in preparation for long-distance flight. Different tissues undergo gene expression changes in keeping with their specialized functions and driven by tissue specific transcriptional pathways. Peroxisome proliferator-activated receptors (PPARs) are lipid-activated nuclear receptors that regulate metabolic pathways involved in lipid and glucose utilization or storage in mammals. To examine whether PPARs might mediate fatty acid activation of metabolic gene programs that would be relevant during pre-migratory fattening, we used gray catbird as the focal species. PPAR isoforms cloned from catbird share high amino acid identity with mammalian homologs (% vs human): gcPPARα (88.1%), gcPPARδ (87.3%), gcPPARγ (91.2%). We tested whether gcPPARs activated fatty acid (FA) utilization genes using Lpl and Cpt1b gene promoter-luciferase reporters in mammalian cell lines. In C2C12 mouse myocytes gcPPARα was broadly activated by the saturated and unsaturated FAs tested; while gcPPARδ showed highest activation by the mono-unsaturated FA, 18:1 oleic acid (+80%). In CV-1 monkey kidney cells gcPPARγ responded to the poly-unsaturated fatty acid, 20:5 eicosapentaenoic acid (+60%). Moreover, in agreement with their structural conservation, gcPPARs were activated by isoform selective synthetic agonists similar to the respective mammalian isoform. Adenoviral mediated over-expression of PPARα in C2C12 myocytes induced expression of genes involved in fatty acid transport, including Cd36/Fat, as well as Cpt1b, which mediates a key rate limiting step of mitochondrial β-oxidation. These gene expression changes correlated with increased lipid droplet accumulation in C2C12 myoblasts and differentiated myotubes and enhanced β-oxidation in myotubes. Collectively, the data predict that the PPARs play a conserved role in gray catbirds to regulate lipid metabolism in target tissues that undergo metabolic remodeling throughout the annual migratory cycle.

Constitutively Active Grp1 Promotes Basal Glucose Transport into White Adipose and Enhances Insulin Sensitivity in High-Fat Fed Mice

Insulin-stimulated phosphorylation of Grp1 (general receptor for phosphoinositides; a.k.a Cyth3, cytohesin3) in cultured adipocytes is known to promote recycling of insulin-regulated glucose transporter (Glut4)-containing vesicles from the endosome to plasma membrane, and to enhance glucose uptake thereafter. We found that Cre-dependent expression of a constitutively active form of Grp1 (caGrp1) specifically increased basal glucose uptake into WAT of young chow-fed mice, without altering Akt phosphorylation or insulin-stimulated uptake. Although early growth and glucose homeostasis in chow-fed caGrp1 mice were normal, caGrp1 mice fed a high fat diet (HFD) became markedly less adipose, and showed improved glucose tolerance and insulin sensitivity vs. Cre-negative controls. Fasting insulinemia in HFD-fed caGrp1 mice was lower, whereas circulating adiponectin was higher, and FGF-21 and leptin were unchanged. Hepatic lipid disposition in HFD-fed caGrp1 mice was comparable to that in controls, though circulating and liver free fatty acids were slightly lower. However, epigonadal WAT from caGrp1 mice showed markedly reduced staining for inflammatory marker CD68, and adipocyte size was also significantly greater. Collectively, these features distinguish caGrp1 mice from those with adipose-specific over-expression of Glut4 described by others, but remain compatible with an adipose-specific basis of improved systemic insulin sensitivity. Given recently improved understanding of the structural/functional changes induced in Grp1 via Akt phosphorylation, drug-based activation of Grp1 in WAT might prove an attractive route by which to favorably alter systemic insulin sensitivity and glycemia. Disclosure K.D. Copps: None. J. Li: None.

Mitophagy Receptor FUNDC1 Links Mitochondrial Quality Control to Muscle–Adipose Dialogue in Alleviating Dietary Obesity

The quality of mitochondria in skeletal muscle is essential for maintaining metabolic homeostasis during adaptive stress responses. However, the precise control mechanism of muscle mitochondrial quality and its physiological impacts remain unclear. Here, using two independent skeletal muscle-specific knockout mouse lines, we demonstrate that FUNDC1, a mediator of mitophagy, plays an essential role in controlling muscle mitochondrial quality as well as metabolic homeostasis. Mice with FUNDC1 deficiency in skeletal muscle (FUNDC1 mKO) showed decreased muscle fat utilization and endurance capacity (∼40%) compared to WT littermates during exercise. Analysis of biochemical markers of mitophagy revealed a marked decrease in mitochondrial localization of LC3-II and P62 protein levels, and this caused impaired mitochondrial respiration capacity. FUNDC1 loss-of-function studies in primary skeletal myocyte recapitulated defective mitophagy and impaired mitochondrial energetic as observed in FUNDC1 mKO muscle. Surprisingly, mice lacking muscle FUNDC1 were resistant to high fat diet (HFD) induced obesity despite reduced muscle mitochondrial energetics. Moreover, glucose and insulin tolerance tests demonstrated that HFD-fed FUNDC1 mKO mice were more tolerant to glucose challenge and more sensitive to insulin stimulation compared to HFD-fed WT controls. This seemingly paradoxical phenotype was due to enhanced fat burning in in adipose tissue. HFD-fed FUNDC1 mKO mice had markedly elevated expression of key thermogenic genes such as Ucp1 (17-fold), Cidea (13-fold), and Dio2 (9-fold) in white adipose. Mechanistically, FUNDC1 deficiency elicited a retrograde response in muscle that upregulated FGF-21 expression, thereby promoting the thermogenic remodeling of adipose tissue. Thus, these findings reveal a pivotal role of FUNDC1-dependent mitochondrial quality-control in mediating the muscle-adipose dialogue to regulate systemic metabolism. Disclosure T. Fu: None. Z. Xu: None. L. Liu: None. X. Liang: None. D. Zhou: None. Q. Guo: None. L. Xiao: None. Z. Gan: None.

The Sarcoplasmic Reticulum Calcium ATPase Pump Is a Major Regulator of Whole–Body Glucose Metabolism

The heart is a very active metabolic organ which exerts endocrine effects by secreting natriuretic peptides. However, its role in the regulation of whole-body metabolism has received scarce attention. Therefore, we hypothesized that cardiac-specific overexpression of the sarcoplasmic reticulum calcium ATPase (SERCA) pump, which tightly regulates cytosolic calcium, modulates whole-body glucose homeostasis during healthy and diabetic states. Diabetes was induced by streptozotocin injections in wild type (WT) and transgenic (TG) mice overexpressing the SERCA pump in the heart (n=4-10/group). Translocation of glucose transporters (GLUTs) was measured in insulin-sensitive tissues using a photolabeled biotinylation assay. The cardiac secretome function was analyzed by mass spectrometry. We reported that blood glucose concentration was lower in diabetic TG mice compared to diabetic WT mice (p=0.023). Cell surface GLUT-4 and -8 protein content was downregulated in the heart of WT diabetic vs. healthy mice (by 56% and 71%, p=0.01 and p<0.001, respectively), which was rescued in TG diabetic mice. In addition, diabetes induced a downregulation of cell surface GLUT4 trafficking in skeletal muscle, and white and brown adipose tissue of WT mice (by 79%, 68% and 74%, respectively, P<0.05), which was restored in TG diabetic mice. We further identified 28 and 32 candidate proteins that have a high probability (i.e., > 95%) of being secreted by the ventricle and atria of TG mice, respectively. Of these, 13 and 10 potentially secreted proteins by the atria and ventricle, respectively, were involved in metabolic processes. In conclusion, these data suggest that cardiac-specific SERCA overexpression rescued hyperglycemia by improving glucose transport in insulin-sensitive tissues of diabetic TG mice. Insights gained from this study could identify the SERCA pump and its secreted proteins as novel pharmacological targets to regulate glucose homeostasis in diabetic patients. Disclosure Z. Maria: None. A. Campolo: None. S. Shoop Gray: None. S. Hartson: None. V. Lacombe: None.

A novel nutrient blend mimics calorie restriction transcriptomics in multiple tissues of mice and increases vitality and lifespan in C. elegans

Identification of caloric restriction mimetics (CRMs), compounds that mimic the beneficial effects of caloric restriction (CR) without limiting energy intake would be a scientific advancement. This study investigated transcriptomics elicited by a putative CRM nutrient blend compared to CR in diverse tissues following long-term feeding in 4 groups of B6C3F1 mice: Young Controls (YC; 5 months) and 3 groups treated from 14–30 months: Old Controls (OC), Old CR (OCR; 25% CR) and Old Supplemented (OS). Gene expression profiling in cerebral cortex (CC), skeletal muscle (SKL), heart (HRT), white adipose (WAT)and liver (LVR) was performed with Affymetrix Mouse 2.0ST arrays. This was followed by a dose-response study in C. elegans investigating longevity and mobility. Principal component analysis revealed that gene expression profiles of YC and OC were distinct from one another in all tissues except WAT at 30 months. The OS mimicked OCR transcriptomics most dramatically in tissues most relevant to aging and age-associated diseases, CCT, HRT and SKL. In C. elegans, the blend mimicked the known benefits of CR, increasing lifespan and vitality in a dose-dependent manner. These CRM effects may have positive implications for healthy human aging or ‘youthspan’ and warrant further investigation.

Increased Ifi202b/IFI16 expression stimulates adipogenesis in mice and humans

Aims/hypothesisObesity results from a constant and complex interplay between environmental stimuli and predisposing genes. Recently, we identified the IFN-activated gene Ifi202b as the most likely gene responsible for the obesity quantitative trait locus Nob3 (New Zealand Obese [NZO] obesity 3). The aim of this study was to evaluate the effects of Ifi202b on body weight and adipose tissue biology, and to clarify the functional role of its human orthologue IFI16.MethodsThe impact of Ifi202b and its human orthologue IFI16 on adipogenesis was investigated by modulating their respective expression in murine 3T3-L1 and human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocytes. Furthermore, transgenic mice overexpressing IFI202b were generated and characterised with respect to metabolic traits. In humans, expression levels of IFI16 in adipose tissue were correlated with several variables of adipocyte function.ResultsIn mice, IFI202b overexpression caused obesity (Δ body weight at the age of 30 weeks: 10.2 ± 1.9 g vs wild-type mice) marked by hypertrophic fat mass expansion, increased expression of Zfp423 (encoding the transcription factor zinc finger protein [ZFP] 423) and white-selective genes (Tcf21, Tle3), and decreased expression of thermogenic genes (e.g. Cidea, Ucp1). Compared with their wild-type littermates, Ifi202b transgenic mice displayed lower body temperature, hepatosteatosis and systemic insulin resistance. Suppression of IFI202b/IFI16 in pre-adipocytes impaired adipocyte differentiation and triacylglycerol storage. Humans with high levels of IFI16 exhibited larger adipocytes, an enhanced inflammatory state and impaired insulin-stimulated glucose uptake in white adipose tissue.Conclusions/interpretationOur findings reveal novel functions of Ifi202b and IFI16, demonstrating their role as obesity genes. These genes promote white adipogenesis and fat storage, thereby facilitating the development of obesity-associated insulin resistance.