scholarly journals Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

2021 ◽  
Author(s):  
Mario Gomez Salazar ◽  
Iris Pruñonosa Cervera ◽  
Rongling Wang ◽  
Karen French ◽  
Ruben García-Martín ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Energy Expenditure ◽  
Therapeutic Strategy ◽  
Oxygen Sensor ◽  
Modern Human ◽  
Protein Levels ◽  
Serum Proteomics ◽  
Potential Biomarker ◽  
Brown Adipose ◽  
Increased Risk

AbstractEnhancing brown adipose tissue (BAT) function to combat metabolic disease is a promising therapeutic strategy. A major obstacle to this strategy is that a thermoneutral environment, relevant to most modern human living conditions, deactivates functional BAT. We showed that we can overcome the dormancy of BAT at thermoneutrality by inhibiting the main oxygen sensor HIF-prolyl hydroxylase, PHD2, specifically in adipocytes. Mice lacking adipocyte PHD2 (P2KOad) and housed at thermoneutrality maintained greater BAT mass, had detectable UCP1 protein expression in BAT and higher energy expenditure. Mouse brown adipocytes treated with the pan-PHD inhibitor, FG2216, exhibited higher Ucp1 mRNA and protein levels, effects that were abolished by antagonising the canonical PHD2 substrate, HIF-2a. Induction of UCP1 mRNA expression by FG2216, was also confirmed in human adipocytes isolated from obese individuals. Human serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study revealed that serum PHD2 (aka EGLN1) associates with increased risk of metabolic disease. Our data suggest adipose–selective PHD2 inhibition as a novel therapeutic strategy for metabolic disease and identify serum PHD2 as a potential biomarker.

scholarly journals CRISPR-delivery particles targeting nuclear receptor–interacting protein 1 (Nrip1) in adipose cells to enhance energy expenditure

2018 ◽  
Vol 293 (44) ◽  
pp. 17291-17305 ◽  
Author(s):  
Yuefei Shen ◽  
Jessica L. Cohen ◽  
Sarah M. Nicoloro ◽  
Mark Kelly ◽  
Batuhan Yenilmez ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Energy Expenditure ◽  
Therapeutic Strategy ◽  
Gene Deletion ◽  
Cultured Cells ◽  
Uncoupling Protein ◽  
Acid Oxidation ◽  
Amphipathic Peptide ◽  
Cas9 Protein

RNA-guided, engineered nucleases derived from the prokaryotic adaptive immune system CRISPR-Cas represent a powerful platform for gene deletion and editing. When used as a therapeutic approach, direct delivery of Cas9 protein and single-guide RNA (sgRNA) could circumvent the safety issues associated with plasmid delivery and therefore represents an attractive tool for precision genome engineering. Gene deletion or editing in adipose tissue to enhance its energy expenditure, fatty acid oxidation, and secretion of bioactive factors through a “browning” process presents a potential therapeutic strategy to alleviate metabolic disease. Here, we developed “CRISPR-delivery particles,” denoted CriPs, composed of nano-size complexes of Cas9 protein and sgRNA that are coated with an amphipathic peptide called Endo-Porter that mediates entry into cells. Efficient CRISPR-Cas9–mediated gene deletion of ectopically expressed GFP by CriPs was achieved in multiple cell types, including a macrophage cell line, primary macrophages, and primary pre-adipocytes. Significant GFP loss was also observed in peritoneal exudate cells with minimum systemic toxicity in GFP-expressing mice following intraperitoneal injection of CriPs containing Gfp-targeting sgRNA. Furthermore, disruption of a nuclear co-repressor of catabolism, the Nrip1 gene, in white adipocytes by CriPs enhanced adipocyte browning with a marked increase of uncoupling protein 1 (UCP1) expression. Of note, the CriP-mediated Nrip1 deletion did not produce detectable off-target effects. We conclude that CriPs offer an effective Cas9 and sgRNA delivery system for ablating targeted gene products in cultured cells and in vivo, providing a potential therapeutic strategy for metabolic disease.

scholarly journals Antioxidant effects of N-acetylcysteine prevent programmed metabolic disease in mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Maureen J. Charron ◽  
Lyda Williams ◽  
Yoshinori Seki ◽  
Xiu Quan Du ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Disease ◽  
Adipose Tissue ◽  
Postnatal Growth ◽  
In Utero ◽  
Leptin Resistance ◽  
Maternal Weight ◽  
Insulin Tolerance ◽  
Brown Adipose ◽  
Increased Risk

An adverse maternal <i>in utero</i> environment can program offspring for increased risk for metabolic disease. The aim of this study was to determine whether N-acetylcysteine (NAC), an anti-inflammatory antioxidant, attenuates programmed susceptibility to obesity and insulin resistance in high fat diet (HFD) offspring. CD1 female mice were acutely fed a standard breeding chow or HFD. NAC was added to the drinking water (1g/kg) of the treatment cohorts from embryonic day 0.5 (e0.5) until the end of lactation. NAC treatment normalized HFD-induced maternal weight gain and oxidative stress, improved the maternal lipidome and prevented maternal leptin resistance. These favorable changes in the <i>in utero</i> environment normalized postnatal growth, decreased white adipose tissue (WAT) and hepatic fat, improved glucose and insulin tolerance and antioxidant capacity, reduced leptin and insulin and increased adiponectin in HFD offspring. The lifelong metabolic improvements in the offspring were accompanied by reductions in pro-inflammatory gene expression in liver and WAT and increased thermogenic gene expression in brown adipose tissue (BAT). These results, for the first time, provide a mechanistic rationale for how NAC can prevent the onset of metabolic disease in the offspring of mothers who consume a typical Western HFDs.

scholarly journals Adipose depot-specific upregulation of Ucp1 or mitochondrial oxidative complex proteins are early consequences of genetic insulin reduction in mice

2020 ◽  
Vol 319 (3) ◽  
pp. E529-E539
Author(s):  
Jose Diego Botezelli ◽  
Peter Overby ◽  
Lorenzo Lindo ◽  
Su Wang ◽  
Obélia Haïda ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Tissue Expansion ◽  
Inhibitory Effect ◽  
Protein Levels ◽  
Low Fat Diet ◽  
Specific Effects ◽  
Brown Adipose

Hyperinsulinemia plays a causal role in adipose tissue expansion. Mice with reduced insulin have increased energy expenditure, but the mechanisms remained unclear. Here we investigated the effects of genetically reducing insulin production on uncoupling and oxidative mitochondrial proteins in liver, skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). Male Ins1+/+ or Ins1+/− littermates were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 4 wk, starting at 8 wk of age. Replicating our previous observations, HFD increased fasting hyperinsulinemia, and Ins1+/− mice had significantly lower circulating insulin compared with Ins1+/+ littermates. Fasting glucose and body weight were not different between genotypes. We did not observe robust significant differences in liver or skeletal muscle. In mesenteric WAT, Ins1+/− mice had reduced Ndufb8 and Sdhb, while Ucp1 was increased in the context of HFD. HFD alone had a dramatic inhibitory effect on Pparg abundance. In inguinal WAT, Ins1+/− mice exhibited significant increases in oxidative complex proteins, independent of diet, without affecting Ucp1, Pparg, or Prdm16:Pparg association. In BAT, lowered insulin increased Sdhb protein levels that had been reduced by HFD. Ucp1 protein, Prdm16:Pparg association, and Sirt3 abundance were all increased in the absence of diet-induced hyperinsulinemia. Our data show that reducing insulin upregulates oxidative proteins in inguinal WAT without affecting Ucp1, whereas in mesenteric WAT and BAT, reducing insulin upregulates Ucp1 in the context of HFD. Preventing hyperinsulinemia has early depot-specific effects on adipose tissue metabolism and helps explain the increased energy expenditure previously reported in Ins1+/− mice.

scholarly journals A Mix of Natural Bioactive Compounds Reduces Fat Accumulation and Modulates Gene Expression in the Adipose Tissue of Obese Rats Fed a Cafeteria Diet

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3251
Author(s):  
Albert Gibert-Ramos ◽  
Miguel Z. Martín-González ◽  
Anna Crescenti ◽  
M. Josepa Salvadó
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Fat Oxidation ◽  
Grape Seed ◽  
Protein Levels ◽  
Expression Of Genes ◽  
Brown Adipose ◽  
Obese Rats ◽  
The Individual

Scientists are focusing on bioactive ingredients to counteract obesity. We evaluated whether a mix containing grape seed proanthocyanidin extract (GSPE), anthocyanins, conjugated linoleic acid (CLA), and chicken feet hydrolysate (CFH) could reduce body fat mass and also determined which mechanisms in the white adipose tissue (WAT) and the brown adipose tissue (BAT) were affected by the treatment. The mix or vehicle (VH) were administered for three weeks to obese rats fed a cafeteria (CAF) diet. Biometric measures, indirect calorimetry, and gene expression in WAT and BAT were analyzed as was the histology of the inguinal WAT (IWAT). The individual compounds were also tested in the 3T3-L1 cell line. The mix treatment resulted in a significant 15% reduction in fat (25.01 ± 0.91 g) compared to VH treatment (21.19 ± 1.59 g), and the calorimetry results indicated a significant increase in energy expenditure and fat oxidation. We observed a significant downregulation of Fasn mRNA and an upregulation of Atgl and Hsl mRNA in adipose depots in the group treated with the mix. The IWAT showed a tendency of reduction in the number of adipocytes, although no differences in the total adipocyte area were found. GSPE and anthocyanins modulated the lipid content and downregulated the gene and protein levels of Fasn compared to the untreated group in 3T3-L1 cells. In conclusion, this mix is a promising treatment against obesity, reducing the WAT of obese rats fed a CAF diet, increasing energy expenditure and fat oxidation, and modifying the expression of genes involved in lipid metabolism of the adipose tissue.

scholarly journals Igfbp2 Deletion in Ovariectomized Mice Enhances Energy Expenditure but Accelerates Bone Loss

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4129-4140 ◽  
Author(s):  
Victoria E. DeMambro ◽  
Phuong T. Le ◽  
Anyonya R. Guntur ◽  
David E. Maridas ◽  
Ernesto Canalis ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Bone Loss ◽  
Energy Expenditure ◽  
Fat Mass ◽  
Mitochondrial Respiration ◽  
Fibroblast Growth Factor 21 ◽  
Female Mice ◽  
Protein Levels ◽  
Ovariectomized Mice ◽  
Brown Adipose

Previously, we reported sexually dimorphic bone mass and body composition phenotypes in Igfbp2−/− mice (−/−), where male mice exhibited decreased bone and increased fat mass, whereas female mice displayed increased bone but no changes in fat mass. To investigate the interaction between IGF-binding protein (IGFBP)-2 and estrogen, we subjected Igfbp2 −/− and +/+ female mice to ovariectomy (OVX) or sham surgery at 8 weeks of age. At 20 weeks of age, mice underwent metabolic cage analysis and insulin tolerance tests before killing. At harvest, femurs were collected for microcomputed tomography, serum for protein levels, brown adipose tissue (BAT) and inguinal white adipose tissue (IWAT) adipose depots for histology, gene expression, and mitochondrial respiration analysis of whole tissue. In +/+ mice, serum IGFBP-2 dropped 30% with OVX. In the absence of IGFBP-2, OVX had no effect on preformed BAT; however, there was significant “browning” of the IWAT depot coinciding with less weight gain, increased insulin sensitivity, lower intraabdominal fat, and increased bone loss due to higher resorption and lower formation. Likewise, after OVX, energy expenditure, physical activity and BAT mitochondrial respiration were decreased less in the OVX−/− compared with OVX+/+. Mitochondrial respiration of IWAT was reduced in OVX+/+ yet remained unchanged in OVX−/− mice. These changes were associated with significant increases in Fgf21 and Foxc2 expression, 2 proteins known for their insulin sensitizing and browning of WAT effects. We conclude that estrogen deficiency has a profound effect on body and bone composition in the absence of IGFBP-2 and may be related to changes in fibroblast growth factor 21.

scholarly journals The Receptor-interacting Serine/Threonine Protein Kinase 1 (RIPK1) Regulates Progranulin Levels

2017 ◽  
Vol 292 (8) ◽  
pp. 3262-3272 ◽  
Author(s):  
Amanda R. Mason ◽  
Lisa P. Elia ◽  
Steven Finkbeiner
Keyword(s):  
Protein Kinase ◽  
Therapeutic Strategy ◽  
Mrna Levels ◽  
Gene Encoding ◽  
Translation Rate ◽  
Protein Levels ◽  
Animal Data ◽  
Increased Risk ◽  
Primary Mouse ◽  
Neuro2a Cells

Progranulin (PGRN), a secreted growth factor, is a key regulator of inflammation and is genetically linked to two common and devastating neurodegenerative diseases. Haploinsufficiency mutations in GRN, the gene encoding PGRN, cause frontotemporal dementia (FTD), and a GRN SNP confers significantly increased risk for Alzheimer's disease (AD). Because cellular and animal data indicate that increasing PGRN can reverse phenotypes of both FTD and AD, modulating PGRN level has been proposed as a therapeutic strategy for both diseases. However, little is known about the regulation of PGRN levels. In this study, we performed an siRNA-based screen of the kinome to identify genetic regulators of PGRN levels in a rodent cell-based model system. We found that knocking down receptor-interacting serine/threonine protein kinase 1 (Ripk1) increased both intracellular and extracellular PGRN protein levels by increasing the translation rate of PGRN without affecting mRNA levels. We observed this effect in Neuro2a cells, wild-type primary mouse neurons, and Grn-haploinsufficient primary neurons from an FTD mouse model. We found that the effect of RIPK1 on PGRN is independent of the kinase activity of RIPK1 and occurs through a novel signaling pathway. These data suggest that targeting RIPK1 may be a therapeutic strategy in both AD and FTD.

scholarly journals Adipose depot-specific upregulation of Ucp1 or mitochondrial oxidative complex proteins are early consequences of genetic insulin reduction in mice

2020 ◽  
Author(s):  
Jose Diego Botezelli ◽  
Peter Overby ◽  
Lorenzo Lindo ◽  
Su Wang ◽  
Obélia Haïda ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Tissue Expansion ◽  
Inhibitory Effect ◽  
Protein Levels ◽  
Low Fat Diet ◽  
Specific Effects ◽  
Brown Adipose

AbstractHyperinsulinemia plays a causal role in adipose tissue expansion. Mice with reduced insulin have increased energy expenditure, but the mechanisms remained unclear. Here we investigated the effects of genetically reducing insulin production on uncoupling and oxidative mitochondrial proteins in liver, skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). Male Ins1+/+ or Ins1+/- littermates were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 4 weeks, starting at 8 weeks of age. Replicating our previous observations, HFD increased fasting hyperinsulinemia, and Ins1+/- mice had significantly lower circulating insulin compared with Ins1+/+ littermates. Fasting glucose and body weight were not different between genotypes. We did not observe significant differences in liver in skeletal muscle. In mesenteric WAT, Ins1+/- mice had reduced Ndufb8 and Sdhb. Ucp1 was increased in the context of the HFD, and HFD alone had a dramatic inhibitory effect on Pparg abundance. In inguinal WAT, Ins1+/- mice exhibited significant increases in oxidative complex proteins, independent of diet, without affecting Ucp1, Pparg, or Prdm16:Pparg association. In BAT, lowered insulin increased Sdhb protein levels that had been reduced by HFD. Ucp1 protein, Prdm16:Pparg association, and Sirt3 abundance were all increased in the absence of diet-induced hyperinsulinemia. Our data show that reducing insulin upregulates oxidative proteins in inguinal WAT without affecting Ucp1, while in mesenteric WAT and BAT, reducing insulin upregulates Ucp1 in the context of HFD. Preventing hyperinsulinemia has early depot-specific effects on adipose tissue metabolism and help explain the increased energy expenditure previously reported in Ins1+/- mice.

scholarly journals Eicosapentaenoic Acid Regulates Brown Adipose Tissue Function, Independently of UCP1 (FS11-01-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Mandana Pahlavani ◽  
Latha Ramalingam ◽  
Emily Miller ◽  
Kalhara Menikdiwela ◽  
Shane Scoggin ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Adipose Tissue ◽  
Oxygen Consumption ◽  
Energy Expenditure ◽  
Eicosapentaenoic Acid ◽  
Brown Adipose Tissue ◽  
Metabolic Effects ◽  
High Fat ◽  
Protein Levels ◽  
Brown Adipose

Abstract Objectives Brown adipose tissue (BAT) is a critical tissue in energy expenditure through its specific uncoupling protein 1 (UCP1). We previously reported that mice fed high fat (HF) diet supplemented with eicosapentaenoic acid (EPA) reduced body weight, adiposity, and insulin resistance, and increased UCP1 protein and mRNA levels of other thermogenic markers in BAT at ambient temperature. Hence, we hypothesized that these metabolic effects of EPA on BAT are in part mediated by UCP1. Methods To determine the role of UCP1 in obesity and BAT regulation by EPA, wild type (WT) and UCP1 knockout (KO) B6 male mice were housed at thermoneutral conditions (30°C), previously reported to induce obesity in the KO mice. Mice were fed a high-fat diet (HF, 45% kcal fat) or HF diet supplemented with 36 g/kg of AlaskOmega EPA-enriched fish oil (800 mg/g), kindly provided by Organic Technologies, for up to 14 weeks. We metabolically phenotyped these mice and investigated metabolic and molecular changes in their interscapular BAT. Specifically, we determined effects of UCP1 deficiency and EPA on BAT thermogenic and mitochondrial markers. Results The previously reported beneficial metabolic effects of EPA in WT mice at ambient, including increased UCP1 expression, were attenuated or lost at thermoneutral temperature. EPA reduced weight gain and adiposity, and improved glucose tolerance in KO mice. In both diets (HF and EPA), BAT triglyceride content was increased, while mitochondrial UCP1, COX I and COX IV protein levels were decreased in the KO compared to the WT genotype (P < 0.05). EPA also increased (P < 0.05) mitochondrial DNA/nuclear DNA ratio in the KO mice. Finally, BAT PGC1α at both gene and protein levels along with whole-body oxygen consumption were increased (P < 0.05) by EPA in KO mice. EPA did not alter the calcium cycling-related markers such as sarcoplasmic/endoplasmic reticulum calcium ATPase 2b (Serca2b) and transient receptor potential vanilloid 2 (Trpv2) in any of the genotypes. Conclusions EPA effects on BAT and mitochondrial function are independent of UCP1, and include increased mitochondrial DNA and oxygen consumption, which may be in part relate to increased PGC1α. Additional studies are required to determine fuel or mitochondrial mechanisms by which energy expenditure is increased independently of UCP1. Funding Sources NIH/NCCIH grant # R15AT008879-01A1.

scholarly journals Antioxidant effects of N-acetylcysteine prevent programmed metabolic disease in mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Maureen J. Charron ◽  
Lyda Williams ◽  
Yoshinori Seki ◽  
Xiu Quan Du ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Disease ◽  
Adipose Tissue ◽  
Postnatal Growth ◽  
In Utero ◽  
Leptin Resistance ◽  
Maternal Weight ◽  
Insulin Tolerance ◽  
Brown Adipose ◽  
Increased Risk

An adverse maternal <i>in utero</i> environment can program offspring for increased risk for metabolic disease. The aim of this study was to determine whether N-acetylcysteine (NAC), an anti-inflammatory antioxidant, attenuates programmed susceptibility to obesity and insulin resistance in high fat diet (HFD) offspring. CD1 female mice were acutely fed a standard breeding chow or HFD. NAC was added to the drinking water (1g/kg) of the treatment cohorts from embryonic day 0.5 (e0.5) until the end of lactation. NAC treatment normalized HFD-induced maternal weight gain and oxidative stress, improved the maternal lipidome and prevented maternal leptin resistance. These favorable changes in the <i>in utero</i> environment normalized postnatal growth, decreased white adipose tissue (WAT) and hepatic fat, improved glucose and insulin tolerance and antioxidant capacity, reduced leptin and insulin and increased adiponectin in HFD offspring. The lifelong metabolic improvements in the offspring were accompanied by reductions in pro-inflammatory gene expression in liver and WAT and increased thermogenic gene expression in brown adipose tissue (BAT). These results, for the first time, provide a mechanistic rationale for how NAC can prevent the onset of metabolic disease in the offspring of mothers who consume a typical Western HFDs.

scholarly journals Nutritional Regulation of Human Brown Adipose Tissue

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1748
Author(s):  
Karla J. Suchacki ◽  
Roland H. Stimson
Keyword(s):  
Metabolic Disease ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Therapeutic Potential ◽  
Metabolic Health ◽  
Nutritional Regulation ◽  
Increase Energy Expenditure ◽  
Brown Adipose ◽  
The Impact

The recent identification of brown adipose tissue in adult humans offers a new strategy to increase energy expenditure to treat obesity and associated metabolic disease. While white adipose tissue (WAT) is primarily for energy storage, brown adipose tissue (BAT) is a thermogenic organ that increases energy expenditure to generate heat. BAT is activated upon cold exposure and improves insulin sensitivity and lipid clearance, highlighting its beneficial role in metabolic health in humans. This review provides an overview of BAT physiology in conditions of overnutrition (obesity and associated metabolic disease), undernutrition and in conditions of altered fat distribution such as lipodystrophy. We review the impact of exercise, dietary macronutrients and bioactive compounds on BAT activity. Finally, we discuss the therapeutic potential of dietary manipulations or supplementation to increase energy expenditure and BAT thermogenesis. We conclude that chronic nutritional interventions may represent a useful nonpharmacological means to enhance BAT mass and activity to aid weight loss and/or improve metabolic health.

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