UCP1-independent thermogenesis

2020 ◽  
Vol 477 (3) ◽  
pp. 709-725 ◽  
Author(s):  
Anna Roesler ◽  
Lawrence Kazak
Keyword(s):  
Energy Expenditure ◽  
Therapeutic Potential ◽  
Uncoupling Protein ◽  
Cell Types ◽  
Energy Balance Equation ◽  
The Body ◽  
Protonmotive Force ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Diet Induced Thermogenesis

Obesity results from energy imbalance, when energy intake exceeds energy expenditure. Brown adipose tissue (BAT) drives non-shivering thermogenesis which represents a powerful mechanism of enhancing the energy expenditure side of the energy balance equation. The best understood thermogenic system in BAT that evolved to protect the body from hypothermia is based on the uncoupling of protonmotive force from oxidative phosphorylation through the actions of uncoupling protein 1 (UCP1), a key regulator of cold-mediated thermogenesis. Similarly, energy expenditure is triggered in response to caloric excess, and animals with reduced thermogenic fat function can succumb to diet-induced obesity. Thus, it was surprising when inactivation of Ucp1 did not potentiate diet-induced obesity. In recent years, it has become clear that multiple thermogenic mechanisms exist, based on ATP sinks centered on creatine, lipid, or calcium cycling, along with Fatty acid-mediated UCP1-independent leak pathways driven by the ADP/ATP carrier (AAC). With a key difference between cold- and diet-induced thermogenesis being the dynamic changes in purine nucleotide (primarily ATP) levels, ATP-dependent thermogenic pathways may play a key role in diet-induced thermogenesis. Additionally, the ubiquitous expression of AAC may facilitate increased energy expenditure in many cell types, in the face of over feeding. Interest in UCP1-independent energy expenditure has begun to showcase the therapeutic potential that lies in refining our understanding of the diversity of biochemical pathways controlling thermogenic respiration.

scholarly journals Susceptibility to diet induced obesity at thermoneutral conditions is independent of UCP1

2021 ◽  
Author(s):  
Sebastian Dieckmann ◽  
Akim Strohmeyer ◽  
Monja Willershaeuser ◽  
Stefanie Maurer ◽  
Wolfgang Wurst ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Knockout Mice ◽  
Body Weight Gain ◽  
Uncoupling Protein ◽  
Exon 2 ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Knockout Model

Objective Activation of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) upon cold stimulation leads to substantial increase in energy expenditure to defend body temperature. Increases in energy expenditure after a high caloric food intake, termed diet-induced thermogenesis, are also attributed to BAT. These properties render BAT a potential target to combat diet-induced obesity. However, studies investigating the role of UCP1 to protect against diet-induced obesity are controversial and rely on the phenotyping of a single constitutive UCP1-knockout model. To address this issue, we generated a novel UCP1-knockout model by Cre-mediated deletion of Exon 2 in the UCP1 gene. We studied the effect of constitutive UCP1 knockout on metabolism and the development of diet-induced obesity. Methods UCP1 knockout and wildtype mice were housed at 30°C and fed a control diet for 4-weeks followed by 8-weeks of high-fat diet. Body weight and food intake were monitored continuously over the course of the study and indirect calorimetry was used to determine energy expenditure during both feeding periods. Results Based on Western blot analysis, thermal imaging and noradrenaline test, we confirmed the lack of functional UCP1 in knockout mice. However, body weight gain, food intake and energy expenditure were not affected by deletion of UCP1 gene function during both feeding periods. Conclusion Conclusively, we show that UCP1 does not protect against diet-induced obesity at thermoneutrality. Further we introduce a novel UCP1-KO mouse enabling the generation of conditional UCP1-knockout mice to scrutinize the contribution of UCP1 to energy metabolism in different cell types or life stages.

scholarly journals Reduced Diet-induced Thermogenesis in Apolipoprotein A-IV Deficient Mice

2019 ◽  
Vol 20 (13) ◽  
pp. 3176 ◽  
Author(s):  
Sydney Pence ◽  
Qi Zhu ◽  
Erin Binne ◽  
Min Liu ◽  
Haifei Shi ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Uncoupling Protein ◽  
Dietary Lipid ◽  
Dietary Lipids ◽  
Chow Diet ◽  
Dark Phase ◽  
Apolipoprotein A ◽  
Brown Adipose ◽  
Diet Induced Thermogenesis

In the presence of dietary lipids, both apolipoprotein A-IV (ApoA-IV) production and brown adipose tissue (BAT) thermogenesis are increased. The effect of dietary lipid-induced AproA-IV on BAT thermogenesis and energy expenditure remains unknown. In the present study, we hypothesized that ApoA-IV knockout (ApoA-IV-KO) mice exhibited decreased BAT thermogenesis to affect energy homeostasis. To test this hypothesis, BAT thermogenesis in wildtype (WT) and ApoA-IV-KO mice fed either a standard low-fat chow diet or a high-fat diet (HFD) was investigated. When fed a chow diet, energy expenditure and food intake were comparable between WT and ApoA-IV-KO mice. After 1 week of HFD consumption, ApoA-IV-KO mice had comparable energy intake but produced lower energy expenditure relative to their WT controls in the dark phase. After an acute feeding of dietary lipids or 1-week HFD feeding, ApoA-IV-KO mice produced lower levels of uncoupling protein 1 (UCP1) and exhibited reduced expression of thermogenic genes in the BAT compared with WT controls. In response to cold exposure, however, ApoA-IV-KO mice had comparable energy expenditure and BAT temperature relative to WT mice. Thus, ApoA-IV-KO mice exhibited reduced diet-induced BAT thermogenesis and energy expenditure.

scholarly journals Susceptibility to diet-induced obesity at thermoneutral conditions is independent of UCP1

2021 ◽  
Author(s):  
Sebastian Dieckmann ◽  
Akim Strohmeyer ◽  
Monja Willershäuser ◽  
Stefanie F. Maurer ◽  
Wolfgang Wurst ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Knockout Mice ◽  
Body Weight Gain ◽  
Uncoupling Protein ◽  
Exon 2 ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Knockout Model

Objective Activation of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) upon cold stimulation leads to substantial increase in energy expenditure to defend body temperature. Increases in energy expenditure after a high caloric food intake, termed diet-induced thermogenesis, are also attributed to BAT. These properties render BAT a potential target to combat diet-induced obesity. However, studies investigating the role of UCP1 to protect against diet-induced obesity are controversial and rely on the phenotyping of a single constitutive UCP1-knockout model. To address this issue, we generated a novel UCP1-knockout model by Cre-mediated deletion of Exon 2 in the UCP1 gene. We studied the effect of constitutive UCP1 knockout on metabolism and the development of diet-induced obesity. Methods UCP1 knockout and wildtype mice were housed at 30°C and fed a control diet for 4-weeks followed by 8-weeks of high-fat diet. Body weight and food intake were monitored continuously over the course of the study and indirect calorimetry was used to determine energy expenditure during both feeding periods. Results Based on Western blot analysis, thermal imaging and noradrenaline test, we confirmed the lack of functional UCP1 in knockout mice. However, body weight gain, food intake and energy expenditure were not affected by deletion of UCP1 gene function during both feeding periods. Conclusion We introduce a novel UCP1-KO mouse enabling the generation of conditional UCP1-knockout mice to scrutinize the contribution of UCP1 to energy metabolism in different cell types or life stages. Our results demonstrate that UCP1 does not protect against diet-induced obesity at thermoneutrality.

Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats

1994 ◽  
Vol 266 (4) ◽  
pp. R1371-R1382 ◽  
Author(s):  
J. Himms-Hagen ◽  
J. Cui ◽  
E. Danforth ◽  
D. J. Taatjes ◽  
S. S. Lang ◽  
...  
Keyword(s):  
Energy Balance ◽  
Energy Expenditure ◽  
Dna Content ◽  
Early Stage ◽  
Uncoupling Protein ◽  
Resting Metabolic Rate ◽  
Cell Types ◽  
Adipose Tissues ◽  
Diet Induced Obesity ◽  
Cl 316,243

The objective was to assess the effect of a new, highly selective beta 3-adrenergic agonist, CL-316,243 (CL) (J. D. Bloom, M. D. Dutia, B. D. Johnson, A. Wissner, M. G. Burns, E. E. Largis, J. A. Dolan, and T. H. Claus., J. Med. Chem. 35: 3081, 1992), on energy balance and brown and white adipose tissues (BAT and WAT, respectively) in young rats eating a high-fat diet to induce obesity. Chronic treatment with CL increased body temperature and 24-h energy expenditure, mainly by increasing resting metabolic rate. Food intake was not altered but carcass fat was reduced. Interscapular BAT was markedly hypertrophied, with three- to fourfold increases in the content of uncoupling protein (UCP) and cytochrome oxidase. Quantitative immunoelectron microscopy of interscapular BAT of CL-treated rats showed smaller mitochondria with an unchanged total amount of UCP per mitochondrion. The relative frequency of the four major cell types in BAT (mature brown adipocytes, preadipocytes, interstitial cells, endothelial cells) was not altered. The CL-induced hypertrophy differed from that induced by chronic stimulation by endogenous norepinephrine (as in cold-adaptation) in absence of hyperplasia (there was a slightly reduced DNA content), absence of an increase in the thyroxine (T4) 5'-deiodinase activity, and absence of a selective increase in UCP concentration. WAT depots weighed less and had fewer cells (lower DNA content) in the CL-treated rats. Some multilocular adipocytes appeared in these normally almost exclusively unilocular WAT depots (mesenteric, inguinal, epididymal, retroperitoneal). We conclude that CL not only promotes BAT mitochondrial proliferation and thermogenesis and overall energy expenditure and leanness, but also retards the development of WAT hyperplasia during the early stage of diet-induced obesity.

scholarly journals DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haiyan Zhou ◽  
Xinyi Peng ◽  
Jie Hu ◽  
Liwen Wang ◽  
Hairong Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Adipose Tissue ◽  
T Cell ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Whole Body ◽  
Brown Adipose ◽  
Ifn Γ ◽  
Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

Abstract 400: Cannabinoid 1 Receptor Blockade Diminishes Obesity and Dyslipidemia via Peripheral Activation of Brown Adipose Tissue

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jimmy F Berbée ◽  
Mariëtte R Boon ◽  
Andrea D van Dam ◽  
Anita M van den Hoek ◽  
Marc Lombès ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Therapeutic Potential ◽  
Lipoprotein Metabolism ◽  
Special Focus ◽  
Cannabinoid 1 Receptor ◽  
Brown Adipose ◽  
Major Player ◽  
Peripheral Activation

Objectives: The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintained weight loss and reduction of dyslipidemia in experimental and human obesity. Brown adipose tissue (BAT) that burns lipids towards heat using UCP1, recently emerged as a major player in lipoprotein metabolism and is present and active in human adults. The aim of the present study was to elucidate the mechanism by which CB1R blockade reverses dyslipidemia and obesity, with special focus on BAT. Methods and results: Diet-induced obese APOE*3-Leiden.CETP transgenic mice, a well-established model for human-like lipoprotein metabolism, were treated with the systemic CB1R blocker rimonabant (10 mg/kg/day) for 4 weeks. Rimonabant persistently decreased body weight (-25%, p<0.001), fat mass (-32%, p<0.001) and plasma triglyceride (TG) levels (-60%, p<0.05), despite a modest and transient reduction in food intake. Interestingly, rimonabant reduced plasma TG levels, not by affecting VLDL-TG production by the liver, but rather by selectively increasing VLDL-TG clearance by BAT (+40%, p<0.05). This was accompanied by increased energy expenditure (+20%, p<0.05), decreased lipid droplet size and increased UCP1 content in BAT (+28%, p<0.05), all pointing to increased BAT activity. Next, we demonstrated that the CB1R is highly expressed in BAT and that in vitro blockade of the CB1R in cultured brown adipocytes resulted in 2.5-fold upregulation of UCP1. Importantly, the in vivo results could be fully recapitulated using the strictly peripheral CB1R antagonist AM6545 (10 mg/kg/day) that does not induce hypophagia. Conclusion: CB1R blockade reduces dyslipidemia and obesity by peripheral activation of BAT. Selective targeting of peripheral CB1R in BAT has thus great therapeutic potential in decreasing dyslipidemia and obesity and ultimately cardiovascular diseases.

scholarly journals Increased Energy Expenditure and Protection from Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9

2021 ◽  
Author(s):  
Ryan P. Ceddia ◽  
Dianxin Liu ◽  
Fubiao Shi ◽  
Mark K. Crowder ◽  
Sumita Mishra ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Second Messengers ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Elevated Expression ◽  
Obesity In Mice ◽  
Ucp1 Expression ◽  
Global Increase ◽  
Fat Diets

Cyclic nucleotides, cAMP and cGMP, are important second messengers for the regulation of adaptive thermogenesis. Their levels are controlled not only by their synthesis but also their degradation. Since pharmacological inhibitors of cGMP-specific phosphodiesterase 9 (PDE9) can increase PKG signaling and UCP1 expression in adipocytes, we sought to elucidate the role of PDE9 on energy balance and glucose homeostasis <i>in vivo</i>. Mice with targeted disruption of the PDE9 gene, <i>Pde9a</i>, were fed nutrient matched high-fat (HFD) or low-fat diets (LFD). <i>Pde9a</i><sup>‑/‑</sup> mice were resistant to HFD induced obesity, exhibiting a global increase in energy expenditure, while brown adipose tissue (AT) had increased respiratory capacity and elevated expression of <i>Ucp1 </i>and other thermogenic genes. Reduced adiposity of HFD-fed <i>Pde9a</i><sup>‑/‑</sup> mice was associated with improvements in glucose handling and hepatic steatosis. Cold exposure or treatment with β-adrenergic receptor agonists markedly decreased <i>Pde9a</i> expression in brown AT and cultured brown adipocytes, while <i>Pde9a<sup>‑/‑</sup></i> mice exhibited a greater increase in AT browning; together suggesting that the PDE9-cGMP pathway augments classical cold-induced β-adrenergic/cAMP AT browning and energy expenditure. These findings suggest PDE9 is a previously unrecognized regulator of energy metabolism and that its inhibition may be a valuable avenue to explore for combating metabolic disease.

scholarly journals Exposure to the Widely Used Pyrethroid Pesticide Deltamethrin, Does Not Exacerbate High Fat Diet Induced Obesity or Insulin Resistance in C57BL/6J Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A45-A46
Author(s):  
Evangelia Evelyn Tsakiridis ◽  
Marisa Morrow ◽  
Andrea Llanos ◽  
Bo Wang ◽  
Alison Holloway ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glycemic Control ◽  
Metabolic Diseases ◽  
Uncoupling Protein ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Pyrethroid Pesticide ◽  
First Time

Abstract Deltamethrin is a commonly used pesticide for the control of mosquito populations. Despite widespread use, the effects of deltamethrin on adiposity and glucose homeostasis have been equivocal with some studies showing increased, decreased and no effect on adiposity and glycemic control. However, no study to date has investigated the effect of deltamethrin in mice housed at thermoneutral temperatures, which is important for modelling metabolic diseases in rodents due to reduced thermal stress and constitutive activation of brown adipose tissue. In the current study we demonstrate for the first time that deltamethrin reduces uncoupling protein-1 expression in brown adipocytes cultured in vitro at concentrations as low as 1pm. Meanwhile, in-vivo deltamethrin does not appear to alter glycemic control or promote adiposity at exposures equivalent to 0.01, 0.1 or 1.0 mg/kg/day. Together, our study demonstrates environmentally relevant exposure to deltamethrin does not exacerbate diet induced obesity or insulin resistance.

scholarly journals Knockout of inositol-requiring enzyme 1α in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure

Open Biology ◽  
2016 ◽  
Vol 6 (8) ◽  
pp. 160131 ◽  
Author(s):  
Yuzhong Xiao ◽  
Tingting Xia ◽  
Junjie Yu ◽  
Yalan Deng ◽  
Hao Liu ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Liver Steatosis ◽  
Leptin Resistance ◽  
Hormone Production ◽  
Melanocyte Stimulating Hormone ◽  
Diet Induced Obesity ◽  
Brown Adipose

Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue. Additionally, α-melanocyte-stimulating hormone production was increased in the hypothalamus of PIKO mice. These results demonstrate that IRE1α in POMC neurons plays a critical role in the regulation of obesity and obesity-related metabolic disorders. Our results also suggest that IRE1α is not only an endoplasmic reticulum stress sensor, but also a new potential therapeutic target for obesity and obesity-related metabolic diseases.

scholarly journals Non-Viable Lactobacillus johnsonii JNU3402 Protects against Diet-Induced Obesity

Foods ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 1494
Author(s):  
Garam Yang ◽  
Eunjeong Hong ◽  
Sejong Oh ◽  
Eungseok Kim
Keyword(s):  
Adipose Tissue ◽  
Body Weight Gain ◽  
Normal Diet ◽  
The Body ◽  
Peroxisome Proliferator ◽  
Lactobacillus Johnsonii ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
And Function

In this study, the role of non-viable Lactobacillus johnsonii JNU3402 (NV-LJ3402) in diet-induced obesity was investigated in mice fed a high-fat diet (HFD). To determine whether NV-LJ3402 exhibits a protective effect against diet-induced obesity, 7-week-old male C57BL/6J mice were fed a normal diet, an HFD, or an HFD with NV-LJ3402 for 14 weeks. NV-LJ3402 administration was associated with a significant reduction in body weight gain and in liver, epididymal, and inguinal white adipose tissue (WAT) and brown adipose tissue weight in HFD-fed mice. Concomitantly, NV-LJ3402 administration to HFD-fed mice also decreased the triglyceride levels in the plasma and metabolic tissues and slightly improved insulin resistance. Furthermore, NV-LJ3402 enhanced gene programming for energy dissipation in the WATs of HFD-fed mice as well as in 3T3-L1 adipocytes with increased peroxisome proliferator-activated receptor-γ (PPARγ) transcriptional activity, suggesting that the PPARγ pathway plays a key role in mediating the anti-obesity effect of NV-LJ3402 in HFD-fed mice. Furthermore, NV-LJ3402 administration in HFD-fed mice enhanced mitochondrial levels and function in WATs and also increased the body temperature upon cold exposure. Together, these results suggest that NV-LJ3402 could be safely used to develop dairy products that ameliorate diet-induced obesity and hyperlipidemia.

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