scholarly journals Augmented CCL5/CCR5 signaling in brown adipose tissue inhibits adaptive thermogenesis and worsens insulin resistance in obesity

2021 ◽  
Author(s):  
Pei-Chi Chan ◽  
Li-Man Hung ◽  
Jiung-Pang Huang ◽  
Yuan-Ji Day ◽  
Chao-Lan Yu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Cold Stress ◽  
Body Weight Gain ◽  
Wild Type ◽  
Double Knockout ◽  
Adaptive Thermogenesis ◽  
Expression Of Genes ◽  
Brown Adipose

Chemokine (C-C motif) ligand 5 (CCL5) and CCR5, one of its receptors have been reported to be highly expressed in white adipose tissue (WAT) and are associated with the progression of inflammation and the development of insulin resistance in obese humans and mice. However, the role of CCL5/CCR5 signaling in obesity-associated dysregulation of energy metabolism remains unclear. Here, we demonstrate that global CCL5/CCR5 double knockout (DKO) mice have higher cold stress-induced energy expenditure and thermogenic function in BAT than wild-type (WT) mice. DKO mice have higher cold stress-induced energy expenditure and thermogenic function in BAT than wild-type mice. KEGG pathway analysis indicated that deletion of CCL5/CCR5 further facilitated the cold-induced expression of genes related to oxidative phosphorylation and lipid metabolic pathways. In primary brown adipocytes of DKO mice, the augmentation of CL-316243-stimulated thermogenic and lipolysis responses was reversed by co-treatment with AMPKα1 and α2 siRNA. Overexpression of BAT CCL5/CCR5 genes by local lentivirus injection in WT mice suppressed cold stress-induced lipolytic processes and thermogenic activities. In contrast, knockdown of BAT CCL5/CCR5 signaling further upregulated AMPK phosphorylation as well as thermogenic and lipolysis responses to chronic adrenergic stimuli and subsequently decreased level of body weight gain. Chronic knockdown of BAT CCL5/CCR5 signaling improved HFD-induced insulin resistance in WT mice. It is suggested that obesity-induced augmentation of AT CCL5/CCR5 signaling could, at least in part, suppress energy expenditure and adaptive thermogenesis by inhibiting AMPK-mediated lipolysis and oxidative metabolism in thermogenic AT to exacerbate the development of obesity and insulin resistance.

Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats

1986 ◽  
Vol 251 (5) ◽  
pp. E576-E583 ◽  
Author(s):  
L. H. Storlien ◽  
D. E. James ◽  
K. M. Burleigh ◽  
D. J. Chisholm ◽  
E. W. Kraegen
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Metabolic Rate ◽  
Brown Adipose Tissue ◽  
Whole Body ◽  
Brown Adipose ◽  
Glucose Output ◽  
Fat Feeding

High levels of dietary fat may contribute to both insulin resistance and obesity in humans but evidence is limited. The euglycemic clamp technique combined with tracer administration was used to study insulin action in vivo in liver and individual peripheral tissues after fat feeding. Basal and nutrient-stimulated metabolic rate was assessed by open-circuit respirometry. Adult male rats were pair-fed isocaloric diets high in either carbohydrate (69% of calories; HiCHO) or fat (59% of calories; HiFAT) for 24 +/- 1 days. Feeding of the HiFAT diet resulted in a greater than 50% reduction in net whole-body glucose utilization at midphysiological insulin levels (90-100 mU/l) due to both reduced glucose disposal and, to a lesser extent, failure to suppress liver glucose output. Major suppressive effects of the HiFAT diet on glucose uptake were found in oxidative skeletal muscles (29-61%) and in brown adipose tissue (BAT; 78-90%), the latter accounting for over 20% of the whole-body effect. There was no difference in basal metabolic rate but thermogenesis in response to glucose ingestion was higher in the HiCHO group. In contrast to their reduced BAT weight, the HiFAT group accumulated more white adipose tissue, consistent with reduced energy expenditure. HiFAT feeding also resulted in major decreases in basal and insulin-stimulated conversion of glucose to lipid in liver (26-60%) and brown adipose tissue (88-90%) with relatively less effect in white adipose (0-43%). We conclude that high-fat feeding results in insulin resistance due mainly to effects in oxidative skeletal muscle and BAT.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract 537: Dock2 Deficiency Mitigates High-Fat Diet-Induced Obesity by Reducing Adipose Tissue Inflammation While Increasing Energy Expenditure

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Xia Guo ◽  
Feifei Li ◽  
Zaiyan Xu ◽  
Shi-You Chen
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Inflammatory Diseases ◽  
Body Weight Gain ◽  
Public Health Problem ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation

Obesity is a public health problem as its association with type 2 diabetes, cardiovascular disorders and many other diseases. Adipose tissue inflammation is frequently observed and plays a vital role in obesity and insulin resistance. Dedicator of cytokinesis 2 (DOCK2) has shown proinflammatory effect in several inflammatory diseases, but its role in obesity remain unknown. To explore the function of DOCK2 in obesity and insulin resistance, wild-type (WT) and DOCK2 knockout (DOCK2-/-) mice were fed with chow or high-fat diet (HFD) for 12 weeks. Metabolic, biochemical and histologic analyses were performed. DOCK2 expression was robustly up-regulated in adipose tissue in WT mice given HFD. DOCK2-/- mice were protected against HFD-enhanced body weight gain with an improved metabolic homeostasis and insulin resistance. In addition, DOCK2 deficiency attenuated adipose tissue and systemic inflammation accompanied by a reduced macrophage infiltration. Moreover, DOCK2 deficiency induced the adipose tissue browning and increased energy expenditure as shown by the up-regulation of metabolic genes in DOCK2-/- mice. Our data indicated that DOCK2 deficiency can protect mice from HFD-induced obesity, metabolic disorders, and insulin resistance. Therefore, targeting DOCK2 may be a potential therapeutic strategy for treating obesity-associated diseases.

scholarly journals CD47 differentially regulates white and brown fat function

Biology Open ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. bio056747
Author(s):  
Heather Norman-Burgdolf ◽  
Dong Li ◽  
Patrick Sullivan ◽  
Shuxia Wang
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
White Adipose Tissue ◽  
Brown Fat ◽  
Chow Diet ◽  
Wild Type ◽  
Comparable Amount ◽  
Brown Adipose ◽  
Deficient Mice

ABSTRACTMechanisms that enhance energy expenditure are attractive therapeutic targets for obesity. Previously we have demonstrated that mice lacking cd47 are leaner, exhibit increased energy expenditure, and are protected against diet-induced obesity. In this study, we further defined the physiological role of cd47 deficiency in regulating mitochondrial function and energy expenditure in both white and brown adipose tissue. We observed that cd47 deficient mice (under normal chow diet) had comparable amount of white fat mass but reduced white adipocyte size as compared to wild-type mice. Subsequent ex vivo and in vitro studies suggest enhanced lipolysis, and not impaired lipogenesis or energy utilization, contributes to this phenotype. In contrast to white adipose tissue, there were no obvious morphological differences in brown adipose tissue between wild-type and knockout mice. However, mitochondria isolated from brown fat of cd47 deficient mice had significantly higher rates of free fatty acid-mediated uncoupling. This suggests that enhanced fuel availability via white adipose tissue lipolysis may perpetuate elevated brown adipose tissue energy expenditure and contributes to the lean phenotype observed in cd47 deficient 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 Brown Adipose Tissue and Its Role in Insulin and Glucose Homeostasis

2021 ◽  
Vol 22 (4) ◽  
pp. 1530
Author(s):  
Katarzyna Maliszewska ◽  
Adam Kretowski
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Glucose Homeostasis ◽  
Uncoupling Protein ◽  
Negative Energy ◽  
Metabolic Complications ◽  
Brown Adipose ◽  
Prevalence Of Obesity

The increased worldwide prevalence of obesity, insulin resistance, and their related metabolic complications have prompted the scientific world to search for new possibilities to combat obesity. Brown adipose tissue (BAT), due to its unique protein uncoupling protein 1 (UPC1) in the inner membrane of the mitochondria, has been acknowledged as a promising approach to increase energy expenditure. Activated brown adipocytes dissipate energy, resulting in heat production. In other words, BAT burns fat and increases the metabolic rate, promoting a negative energy balance. Moreover, BAT alleviates metabolic complications like dyslipidemia, impaired insulin secretion, and insulin resistance in type 2 diabetes. The aim of this review is to explore the role of BAT in total energy expenditure, as well as lipid and glucose homeostasis, and to discuss new possible activators of brown adipose tissue in humans to treat obesity and metabolic disorders.

scholarly journals Dorsomedial hypothalamic BDNF neurons integrate thermal afferent signals to control energy expenditure

2021 ◽  
Author(s):  
Wei L Shen ◽  
Hongbin Sun ◽  
Qian Zhou ◽  
Hao Bian ◽  
Mengting Wang ◽  
...  
Keyword(s):  
Physical Activity ◽  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Energy Expenditure ◽  
Body Weight Gain ◽  
Dorsomedial Hypothalamus ◽  
Brown Adipose ◽  
Thermoregulatory System ◽  
Bdnf Signaling

Mutations in the gene brain-derived neurotrophic factor (BDNF) cause obesity in humans. BDNF signaling and its expressing neurons in the hypothalamus help control feeding, energy expenditure (EE), and physical activity. However, whether the BDNF neurons interact with another EE-regulating system, the thermoregulation circuitry, remains unclear. Here, we show that BDNF neurons in the dorsomedial hypothalamus (DMH) are activated by environmental cooling and sufficient to induce body temperature increases and brown adipose tissue (BAT) thermogenesis. Conversely, blocking these neurons impairs BAT thermogenesis and cold defense, causing body weight gain and glucose intolerance. DMH BDNF neurons are therefore an important type of thermoregulatory neuron, integrating thermal afferent signals to control EE during cold defense. This reveals a critical intersection between the BDNF circuitry and the thermoregulatory system.

199-LB: ATF4 Deletion in Brown Adipose Tissue Impairs Adaptive Thermogenesis but Attenuates Diet-Induced Insulin Resistance

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 199-LB
Author(s):  
SARAH BJORKMAN ◽  
ALEX A. MARTI ◽  
ERIC T. WEATHERFORD ◽  
LUIS M. GARCÍA-PEÑA ◽  
MATTHEW J. POTTHOFF ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Adaptive Thermogenesis ◽  
Brown Adipose

scholarly journals Apolipoprotein CIII Reduction Protects White Adipose Tissues against Obesity-Induced Inflammation and Insulin Resistance in Mice

2021 ◽  
Vol 23 (1) ◽  
pp. 62
Author(s):  
Patricia Recio-López ◽  
Ismael Valladolid-Acebes ◽  
Per-Olof Berggren ◽  
Lisa Juntti-Berggren
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Antisense Oligonucleotide ◽  
High Fat Diet ◽  
High Fat ◽  
Apolipoprotein Ciii ◽  
Expression Of Genes ◽  
Brown Adipose ◽  
Isolated Adipocytes

Apolipoprotein CIII (apoCIII) is proinflammatory and increases in high-fat diet (HFD)-induced obesity and insulin resistance. We have previously shown that reducing apoCIII improves insulin sensitivity in vivo by complex mechanisms involving liver and brown adipose tissue. In this study the focus was on subcutaneous (SAT) and visceral (VAT) white adipose tissue (WAT). Mice were either given HFD for 14 weeks and directly from start also treated with antisense oligonucleotide (ASO) against apoCIII or given HFD for 10 weeks and HFD+ASO for an additional 14 weeks. Both groups had animals treated with inactive (Scr) ASO as controls and in parallel chow-fed mice were injected with saline. Preventing an increase or lowering apoCIII in the HFD-fed mice decreased adipocytes’ size, reduced expression of inflammatory cytokines and increased expression of genes related to thermogenesis and beiging. Isolated adipocytes from both VAT and SAT from the ASO-treated mice had normal insulin-induced inhibition of lipolysis compared to cells from Scr-treated mice. In conclusion, the HFD-induced metabolic derangements in WATs can be prevented and reversed by lowering apoCIII.

scholarly journals SUN-590 27-Hydroxycholesterol Triggers the Whitening of Brown Adipose Tissue

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Arvand Asghari ◽  
Linh Bui ◽  
Robert Stephen ◽  
Michihisa Umetani
Keyword(s):  
Estrogen Receptor ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
White Adipose Tissue ◽  
Vehicle Control ◽  
The Body ◽  
Wild Type ◽  
Brown Adipose

Abstract 27-Hydroxycholesterol (27HC) is the most abundant oxysterol in circulation and metabolized by a P450 enzyme CYP7B1. Its levels closely correspond to those of cholesterol in the body. In addition, previously it was found that 27HC is an endogenous selective estrogen receptor modulator (SERM), which links cholesterol metabolism to estrogen receptor actions (1). Brown adipose tissue (BAT) is the primary source of energy expenditure and energy homeostasis, as well as body temperature maintenance. While previously it was believed that BAT activity is limited to neonates and young children, it is now recognized that BAT is also active in adult humans and its function is impaired by metabolic diseases such as obesity. BAT is also a secretory organ and produces brown adipokines, although the exact function of BAT and adipokines from this tissue in obesity has not been completely understood. Recently, it was reported that 27HC plays an important role in obesity and augments body weight gain in response to a high fat, high cholesterol (HFHC) diet by increasing pre-adipocyte population in the white adipose tissue. 27HC mimics the effects by HFHC diet-feeding on white adipose tissue, such as promoting the inflammation and macrophage infiltration (2). In this study, we explored the effect of 27HC on BAT morphology and function. First, we compared the morphology of BAT from wild-type mice and Cyp7b1-/- mice that have elevated levels of 27HC using H&E staining. Interestingly, brown adipocytes from Cyp7b1-/- mice were larger in cell size than those from wild-type mice, and the cells were mostly unilocular compared to the multilocular cells from wild-type mice, indicating the transition toward a “whitening” phenotype. Next, We treated mice fed a normal chow or a HFHC diet with 27HC or vehicle control for 8 weeks to examine the direct effect by 27HC on BAT. Similar to the phenotype in Cyp7b1-/-mice, 27HC increased the “whitening” of BAT regardless of the diet. We also determined the gene expression of brown adipocyte markers such as UCP1, PGC1a, and DIO2, and found that 27HC significantly decreased the expression of the BAT markers regardless of the diet, confirming the “whitening” observed in the morphology. Moreover, the energy expenditure in mice treated with 27HC was decreased compared to the vehicle control on a HFHC diet, suggesting that 27HC also alters BAT function. These results show that 27HC causes the whitening of BAT, and shed light on the important role of 27HC in brown adipose tissue function. Future experiments will be warranted toward further understanding of the role of 27HC in BAT function. Reference:(1) Umetani, Michihisa, et al. Nature medicine 13.10 (2007): 1185. (2) Asghari, Arvand, et al. Endocrinology 160.10 (2019): 2485-2494.

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