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

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.

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Oleacein Prevents High Fat Diet-Induced A Diposity and Ameliorates Some Biochemical Parameters of Insulin Sensitivity in Mice

Nutrients ◽

10.3390/nu11081829 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1829 ◽

Cited By ~ 8

Author(s):

Lepore ◽

Maggisano ◽

Bulotta ◽

Mignogna ◽

Arcidiacono ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

High Fat Diet ◽

Fatty Acid Synthase ◽

Glucose Transporter ◽

Regulatory Element ◽

Regulatory Elements ◽

High Fat

Oleacein is one of the most abundant polyphenolic compounds of olive oil, which has been shown to play a protective role against several metabolic abnormalities, including dyslipidemia, insulin resistance, and glucose intolerance. Herein, we investigated the effects of oleacein on certain markers of adipogenesis and insulin-resistance in vitro, in 3T3-L1 adipocytes, and in vivo in high-fat diet (HFD)-fed mice. During the differentiation process of 3T3-L1 preadipocytes into adipocytes, oleacein strongly inhibited lipid accumulation, and decreased protein levels of peroxisome proliferator-activated receptor gamma (PPARγ) and fatty acid synthase (FAS), while increasing Adiponectin levels. In vivo, treatment with oleacein of C57BL/6JOlaHsd mice fed with HFD for 5 and 13 weeks prevented the increase in adipocyte size and reduced the inflammatory infiltration of macrophages and lymphocytes in adipose tissue. These effects were accompanied by changes in the expression of adipose tissue-specific regulatory elements such as PPARγ, FAS, sterol regulatory element-binding transcription factor-1 (SREBP-1), and Adiponectin, while the expression of insulin-sensitive muscle/fat glucose transporter Glut-4 was restored in HFD-fed mice treated with oleacein. Collectively, our findings indicate that protection against HFD-induced adiposity by oleacein in mice is mediated by the modulation of regulators of adipogenesis. Protection against HFD-induced obesity is effective in improving peripheral insulin sensitivity.

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Cytochrome P-450 CYP2E1 knockout mice are protected against high-fat diet-induced obesity and insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00258.2011 ◽

2012 ◽

Vol 302 (5) ◽

pp. E532-E539 ◽

Cited By ~ 50

Author(s):

Haihong Zong ◽

Michal Armoni ◽

Chava Harel ◽

Eddy Karnieli ◽

Jeffrey E. Pessin

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Knockout Mice ◽

High Fat Diet ◽

Whole Body ◽

High Fat ◽

Normal Chow ◽

Glucose Output ◽

Fat Diets

Conventional (whole body) CYP2E1 knockout mice displayed protection against high-fat diet-induced weight gain, obesity, and hyperlipidemia with increased energy expenditure despite normal food intake and spontaneous locomotor activity. In addition, the CYP2E1 knockout mice displayed a marked improvement in glucose tolerance on both normal chow and high-fat diets. Euglycemic-hyperinsulinemic clamps demonstrated a marked protection against high-fat diet-induced insulin resistance in CYP2E1 knockout mice, with enhanced adipose tissue glucose uptake and insulin suppression of hepatic glucose output. In parallel, adipose tissue was protected against high-fat diet-induced proinflammatory cytokine production. Taken together, these data demonstrate that the CYP2E1 deletion protects mice against high-fat diet-induced insulin resistance with improved glucose homeostasis in vivo.

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Role of brown adipose tissue in modulating adipose tissue inflammation and insulin resistance in high-fat diet fed mice

European Journal of Pharmacology ◽

10.1016/j.ejphar.2019.02.044 ◽

2019 ◽

Vol 854 ◽

pp. 354-364 ◽

Cited By ~ 7

Author(s):

Kripa Shankar ◽

Durgesh Kumar ◽

Sanchita Gupta ◽

Salil Varshney ◽

Sujith Rajan ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

Adipose Tissue Inflammation ◽

High Fat ◽

Tissue Inflammation ◽

Brown Adipose

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Lowering apolipoprotein CIII protects against high-fat diet–induced metabolic derangements

Science Advances ◽

10.1126/sciadv.abc2931 ◽

2021 ◽

Vol 7 (11) ◽

pp. eabc2931

Author(s):

Ismael Valladolid-Acebes ◽

Karin Åvall ◽

Patricia Recio-López ◽

Noah Moruzzi ◽

Galyna Bryzgalova ◽

...

Keyword(s):

Fatty Acids ◽

Adipose Tissue ◽

High Fat Diet ◽

Hepatic Uptake ◽

Metabolic Phenotype ◽

High Fat ◽

Apolipoprotein Ciii ◽

Brown Adipose ◽

Metabolically Healthy ◽

And Function

Increased levels of apolipoprotein CIII (apoCIII), a key regulator of lipid metabolism, result in obesity-related metabolic derangements. We investigated mechanistically whether lowering or preventing high-fat diet (HFD)–induced increase in apoCIII protects against the detrimental metabolic consequences. Mice, first fed HFD for 10 weeks and thereafter also given an antisense (ASO) to lower apoCIII, already showed reduced levels of apoCIII and metabolic improvements after 4 weeks, despite maintained obesity. Prolonged ASO treatment reversed the metabolic phenotype due to increased lipase activity and receptor-mediated hepatic uptake of lipids. Fatty acids were transferred to the ketogenic pathway, and ketones were used in brown adipose tissue (BAT). This resulted in no fat accumulation and preserved morphology and function of liver and BAT. If ASO treatment started simultaneously with the HFD, mice remained lean and metabolically healthy. Thus, lowering apoCIII protects against and reverses the HFD-induced metabolic phenotype by promoting physiological insulin sensitivity.

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Gene Expression Analysis of Environmental Temperature and High-Fat Diet-Induced Changes in Mouse Supraclavicular Brown Adipose Tissue

Cells ◽

10.3390/cells10061370 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1370

Author(s):

Yufeng Shi ◽

Honglei Zhai ◽

Sharon John ◽

Yi-Ting Shen ◽

Yali Ran ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

High Fat Diet ◽

High Fat ◽

Nutrient Processing ◽

Expression Of Genes ◽

Brown Adipose ◽

Attractive Therapeutic Target

Obesity, a dysregulation of adipose tissue, is a major health risk factor associated with many diseases. Brown adipose tissue (BAT)-mediated thermogenesis can potentially regulate energy expenditure, making it an attractive therapeutic target to combat obesity. Here, we characterize the effects of cold exposure, thermoneutrality, and high-fat diet (HFD) feeding on mouse supraclavicular BAT (scBAT) morphology and BAT-associated gene expression compared to other adipose depots, including the interscapular BAT (iBAT). scBAT was as sensitive to cold induced thermogenesis as iBAT and showed reduced thermogenic effect under thermoneutrality. While both scBAT and iBAT are sensitive to cold, the expression of genes involved in nutrient processing is different. The scBAT also showed less depot weight gain and more single-lipid adipocytes, while the expression of BAT thermogenic genes, such as Ucp1, remained similar or increased more under our HFD feeding regime at ambient and thermoneutral temperatures than iBAT. Together, these findings show that, in addition to its anatomical resemblance to human scBAT, mouse scBAT possesses thermogenic features distinct from those of other adipose depots. Lastly, this study also characterizes a previously unknown mouse deep neck BAT (dnBAT) depot that exhibits similar thermogenic characteristics as scBAT under cold exposure and thermoneutrality.

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The Effect of a Sustained High-Fat Diet on the Metabolism of White and Brown Adipose Tissue and Its Impact on Insulin Resistance: A Selected Time Point Cross-Sectional Study

International Journal of Molecular Sciences ◽

10.3390/ijms222413639 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13639

Author(s):

Babu Raja Maharjan ◽

Susan V. McLennan ◽

Christine Yee ◽

Stephen M. Twigg ◽

Paul F. Williams

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

High Fat Diet ◽

Liver Fat ◽

Lipid Deposition ◽

High Fat ◽

Dynamic Changes ◽

Gene Markers ◽

Fat Depots ◽

Brown Adipose

(1) Background: studies on the long-term dynamic changes in fat depot metabolism in response to a high-fat diet (HFD) on hepatic lipid deposition and insulin resistance are sparse. This study investigated the dynamic changes produced by HFD and the production of dysfunctional fat depots on insulin resistance and liver lipid metabolism. (2) Methods: mice fed a chow or HFD (45% kcal fat) diet had three fat depots, liver, and blood collected at 6, 10, 20, and 30 weeks. Anthropometric changes and gene markers for adipogenesis, thermogenesis, ECM remodeling, inflammation, and tissue insulin resistance were measured. (3) Results: early responses to the HFD were increased body weight, minor deposition of lipid in liver, increased adipocyte size, and adipogenesis. Later changes were dysfunctional adipose depots, increased liver fat, insulin resistance (shown by changes in ITT) accompanied by increased inflammatory markers, increased fibrosis (fibrosis > 2-fold, p < 0.05 from week 6), and the presence of crown cells in white fat depots. Later, changes did not increase thermogenic markers in response to the increased calories and decreased UCP1 and PRDM16 proteins in WAT. (4) Conclusions: HFD feeding initially increased adipocyte diameter and number, but later changes caused adipose depots to become dysfunctional, restricting adipose tissue expansion, changing the brown/beige ratios in adipose depots, and causing ectopic lipid deposition and insulin resistance.

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Adipocyte Utx Deficiency Promotes High-Fat Diet-Induced Metabolic Dysfunction in Mice

Cells ◽

10.3390/cells11020181 ◽

2022 ◽

Vol 11 (2) ◽

pp. 181

Author(s):

Fenfen Li ◽

Shirong Wang ◽

Xin Cui ◽

Jia Jing ◽

Liqing Yu ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Whole Body ◽

Brown Adipocyte ◽

Chow Diet ◽

Main Function ◽

Metabolic Dysfunction ◽

High Fat ◽

Brown Adipose

While the main function of white adipose tissue (WAT) is to store surplus of energy as triacylglycerol, that of brown adipose tissue (BAT) is to burn energy as heat. Epigenetic mechanisms participate prominently in both WAT and BAT energy metabolism. We previously reported that the histone demethylase ubiquitously transcribed tetratricopeptide (Utx) is a positive regulator of brown adipocyte thermogenesis. Here, we aimed to investigate whether Utx also regulates WAT metabolism in vivo. We generated a mouse model with Utx deficiency in adipocytes (AUTXKO). AUTXKO animals fed a chow diet had higher body weight, more fat mass and impaired glucose tolerance. AUTXKO mice also exhibited cold intolerance with an impaired brown fat thermogenic program. When challenged with high-fat diet (HFD), AUTXKO mice displayed adipose dysfunction featured by suppressed lipogenic pathways, exacerbated inflammation and fibrosis with less fat storage in adipose tissues and more lipid storage in the liver; as a result, AUTXKO mice showed a disturbance in whole body glucose homeostasis and hepatic steatosis. Our data demonstrate that Utx deficiency in adipocytes limits adipose tissue expansion under HFD challenge and induces metabolic dysfunction via adipose tissue remodeling. We conclude that adipocyte Utx is a key regulator of systemic metabolic homeostasis.

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A single day of high fat diet feeding induces lipid accumulation and insulin resistance in brown adipose tissue in mice

Atherosclerosis ◽

10.1016/j.atherosclerosis.2020.10.267 ◽

2020 ◽

Vol 315 ◽

pp. e87

Author(s):

M. Modder ◽

E.N. Kuipers ◽

N.M. Held ◽

W. In Het Panhuis ◽

P.M.M. Ruppert ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Lipid Accumulation ◽

High Fat Diet ◽

High Fat ◽

Brown Adipose

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Haploinsufficiency of the retinoblastoma protein gene reduces diet-induced obesity, insulin resistance, and hepatosteatosis in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00163.2009 ◽

2009 ◽

Vol 297 (1) ◽

pp. E184-E193 ◽

Cited By ~ 29

Author(s):

Josep Mercader ◽

Joan Ribot ◽

Incoronata Murano ◽

Søren Feddersen ◽

Saverio Cinti ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

Retinoblastoma Protein ◽

Brown Adipocyte ◽

Wild Type ◽

High Fat ◽

Brown Adipose

Brown adipose tissue activity dissipates energy as heat, and there is evidence that lack of the retinoblastoma protein (pRb) may favor the development of the brown adipocyte phenotype in adipose cells. In this work we assessed the impact of germ line haploinsufficiency of the pRb gene (Rb) on the response to high-fat diet feeding in mice. Rb+/− mice had body weight and adiposity indistinguishable from that of wild-type (Rb+/+) littermates when maintained on a standard diet, yet they gained less body weight and body fat after long-term high-fat diet feeding coupled with reduced feed efficiency and increased rectal temperature. Rb haploinsufficiency ameliorated insulin resistance and hepatosteatosis after high-fat diet in male mice, in which these disturbances were more marked than in females. Compared with wild-type littermates, Rb+/− mice fed a high-fat diet displayed higher expression of peroxisome proliferator-activated receptor (PPAR)γ as well as of genes involved in mitochondrial function, cAMP sensitivity, brown adipocyte determination, and tissue vascularization in white adipose tissue depots. Furthermore, Rb+/− mice exhibited signs of enhanced activation of brown adipose tissue and higher expression levels of PPARα in liver and of PPARδ in skeletal muscle, suggestive of an increased capability for fatty acid oxidation in these tissues. These findings support a role for pRb in modulating whole body energy metabolism and the plasticity of the adipose tissues in vivo and constitute first evidence that partial deficiency in the Rb gene protects against the development of obesity and associated metabolic disturbances.

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A Novel Multi-Ingredient Supplement Activates a Browning Program in White Adipose Tissue and Mitigates Weight Gain in High-Fat Diet-Fed Mice

Nutrients ◽

10.3390/nu13113726 ◽

2021 ◽

Vol 13 (11) ◽

pp. 3726

Author(s):

Joshua P. Nederveen ◽

Katherine Manta ◽

Adam L. Bujak ◽

Alexander C. Simone ◽

Matthew R. Fuda ◽

...

Keyword(s):

Adipose Tissue ◽

Fat Mass ◽

White Adipose Tissue ◽

High Fat Diet ◽

Fatty Acid Transport ◽

Acid Transport ◽

Inflammation Markers ◽

High Fat ◽

Brown Adipose

We investigated the effects of a novel multi-ingredient supplement comprised of polyphenol antioxidants and compounds known to facilitate mitochondrial function and metabolic enhancement (ME) in a mouse model of obesity. In this study, 6-week-old male C57/BL6J mice were placed on a high-fat diet (HFD; ~60% fat) for 6 weeks, with subsequent allocation into experimentalgroups for 4 weeks: HFD control, HFD + ME10 (10 components), HFD + ME7 (7 components), HFD + ME10 + EX, HFD + EX (where ‘+EX’ animals exercised 3 days/week), and chow-fed control. After the intervention, HFD control animals had significantly greater body weight and fat mass. Despite the continuation of HFD, animals supplemented with multi-ingredient ME or who performed exercise training showed an attenuation of fat mass and preservation of lean body mass, which was further enhanced when combined (ME+EX). ME supplementation stimulated the upregulation of white and brown adipose tissue mRNA transcripts associated with mitochondrial biogenesis, browning, fatty acid transport, and fat metabolism. In WAT depots, this was mirrored by mitochodrial oxidative phosphorylation (OXPHOS) protein expression, and increased in vivo fat oxidation measured via CLAMS. ME supplementation also decreased systemic and local inflammation markers. Herein, we demonstrated that novel multi-ingredient nutritional supplements induced significant fat loss independent of physical activity while preserving muscle mass in obese mice. Mechanistically, these MEs appear to act by inducing a browning program in white adipose tissue and decreasing other pathophysiological impairments associated with obesity, including mitochondrial respiration alterations induced by HFD.

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