Major thermogenic defect associated with insulin resistance in brown adipose tissue of obese diabetic SHR/N-cp rats

1991 ◽  
Vol 261 (2) ◽  
pp. E204-E213 ◽  
Author(s):  
A. Marette ◽  
Y. Deshaies ◽  
A. J. Collet ◽  
O. Tulp ◽  
L. J. Bukowiecki
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Shr Rats ◽  
Mitochondrial Content ◽  
Brown Adipocytes ◽  
Ultrastructural Studies ◽  
Brown Adipose ◽  
Large Lipid Droplet ◽  
Phenylisopropyl Adenosine

The effects of norepinephrine and insulin on thermogenesis were investigated in adipocytes isolated from brown adipose tissue (BAT) of obese non-diabetic LA/N-cp rats (obese LA), obese diabetic SHR/N-cp rats (obese SHR), and their corresponding lean controls. The maximal calorigenic response (Vmax) and the sensitivity [50% effective concentration (EC50)] to norepinephrine (1 microM) were markedly reduced in brown adipocytes from obese SHR rats compared with their lean controls (3- to 4-fold decrease in the Vmax and 50% increase in the EC50 value). In the same cells, there was a similar decrease in the respiratory response to dibutyryl adenosine 3',5'-cyclic monophosphate, indicating the presence of a major postreceptor defect. Remarkably, total BAT cytochrome oxidase activity (an index of cellular mitochondrial content) was also diminished three to four times in obese SHR rats, suggesting that a reduced BAT mitochondrial content is responsible for the decreased thermogenesis. Ultrastructural studies revealed that the cytoplasm of brown adipocytes from obese SHR rats contained a large lipid droplet, numerous tiny droplets, and few atypical mitochondria with loosely packed cristae. Adipocytes from obese SHR rats were also characterized by a significant resistance to the antithermogenic effect of insulin but not to that of the nonmetabolizable adenosine analogue N6-phenylisopropyl adenosine. In contrast, all the above biochemical parameters were normal in obese LA rats. These results demonstrate that the marked insulin resistance in BAT of obese SHR rats is associated with a decreased responsiveness and sensitivity to norepinephrine, indicating the presence of receptor and postreceptor defects. It is suggested that insulin resistance and/or diabetes in SHR/N-cp rats lead to a decreased mitochondriogenesis in BAT, which results in a reduced thermogenic capacity, thereby contributing to the development of obesity.

scholarly journals Deregulation of PP2A-Akt Interaction Contributes to Sucrose Non-Fermenting Related Kinase (SNRK) Deficiency Induced Insulin Resistance in Adipose Tissue (P21-071-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jie Li ◽  
Ran An ◽  
Simin Liu ◽  
Haiyan Xu
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Knockout Model ◽  
Potential Substrate

Abstract Objectives Sucrose Non-Fermenting Related Kinase (SNRK), a serine/threonine kinase, is a novel member of the AMPK/SNF1 family. We previously reported that adipose specific SNRK deficiency induced systemic inflammation and insulin resistance. In this study, we aimed to dissect the role of SNRK in white versus brown adipose tissue in insulin signaling and glucose homeostasis. Methods The SNRKloxp/loxp mice were mated with adiponectin-Cre (A-Cre) transgenic mice to generate the adipose tissue specific knockout model (SNRK−/−, A-Cre), and with UCP1-Cre (U-Cre) mice to generate the brown adipose tissue (BAT) specific knockout model (SNRK−/−, U-Cre). RNA sequencing and phosphoproteomics analysis were applied to identify the signaling pathways affected by SNRK deficiency and the potential substrate of SNRK. Results SNRK deletion exclusively in BAT is sufficient to impair insulin signaling and glucose uptake without inducing local and systemic inflammation. Phosphoproteomic study identified PPP2R5D as the potential substrate of SNRK that regulates insulin signaling through controlling PP2A activity. Dephosphorylated PPP2R5D promotes constitutive assembly of PP2A-Akt complex in SNRK deficient primary brown adipocytes and BAT, therefore reduces insulin stimulated Akt phosphorylation and subsequent glucose uptake. RNA sequencing data provided further evidence to show that the PI3K/AKT signaling pathway is suppressed by SNRK deletion in primary brown adipocytes. Conclusions Insulin resistance in BAT alone is not sufficient to impact whole body glucose homeostasis, indicating that the role of SNRK in WAT and inflammation might be critical for observed systemic insulin resistance in SNRK−/−, A-Cre mice. Funding Sources National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK103699).

Guarana supplementation attenuated obesity, insulin resistance, and adipokines dysregulation induced by a standardized human Western diet via brown adipose tissue activation

2019 ◽  
Vol 33 (5) ◽  
pp. 1394-1403 ◽  
Author(s):  
Rafael Calixto Bortolin ◽  
Amanda Rodrigues Vargas ◽  
Vitor Ramos ◽  
Juciano Gasparotto ◽  
Paloma Rodrigues Chaves ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Western Diet ◽  
Brown Adipose

Selective loss of uncoupling protein mRNA in brown adipose tissue on deacclimation of cold-acclimated mice

1987 ◽  
Vol 65 (11) ◽  
pp. 955-959 ◽  
Author(s):  
Hasmukh V. Patel ◽  
Karl B. Freeman ◽  
Michel Desautels
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Cytochrome C Oxidase ◽  
Time Course ◽  
Uncoupling Protein ◽  
Relative Proportion ◽  
Cdna Probe ◽  
Mitochondrial Content ◽  
Brown Adipose ◽  
Uncoupling Protein Mrna

The time course of changes in the level of uncoupling protein mRNA when cold-acclimated mice were returned to a thermoneutral environment (33 °C) was examined using a cDNA probe. Upon deacclimation, there was a marked loss of uncoupling protein mRNA within 24 h, which precedes the loss of uncoupling protein from mitochondria. This loss of uncoupling protein mRNA was selective, since there was no change in the relative proportion of cytochrome c oxidase subunit IV mRNA or poly(A)+ RNA in total RNA. The results suggest that the decrease in the mitochondrial content of uncoupling protein during deacclimation is likely the result of turnover of existing protein, with very little replacement due to a lower level of its mRNA.

The development of insulin resistance in brown adipose tissue may impair the acute cold-induced activation of thermogenesis in genetically obese (ob/ob) mice

1984 ◽  
Vol 4 (11) ◽  
pp. 933-940 ◽  
Author(s):  
Stewart W. Mercer ◽  
Paul Trayhurn
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Cold Exposure ◽  
Brown Fat ◽  
Acute Cold Exposure ◽  
Brown Adipose

Genetically obese (ob/ob) mice develop insulin resistance in brown adipose tissue during the fifth week of life. Prior to this, at 26 days of age, oh/oh mice show a substantial increase in GDP binding to brownadipose-tissue mitochondria during acute cold exposure. When insulin resistance in brown fat develops, by 35 days of age, the increase in GDP binding in response to cold is markedly reduced. Studies with 2-deoxyglucose suggest that insulin resistance in brown adipose tissue could impair thermogenic responsiveness during acute cold exposure by limiting the ability of the tissue to take up glucose.

scholarly journals Peroxisome Proliferator-Activated Receptors-α and -γ, and cAMP-Mediated Pathways, Control Retinol-Binding Protein-4 Gene Expression in Brown Adipose Tissue

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1162-1173 ◽  
Author(s):  
Meritxell Rosell ◽  
Elayne Hondares ◽  
Sadahiko Iwamoto ◽  
Frank J. Gonzalez ◽  
Martin Wabitsch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Retinol Binding Protein ◽  
Peroxisome Proliferator ◽  
Brown Adipocytes ◽  
Retinol Binding Protein 4 ◽  
White Adipocytes ◽  
Brown Adipose ◽  
Rbp4 Gene

Retinol binding protein-4 (RBP4) is a serum protein involved in the transport of vitamin A. It is known to be produced by the liver and white adipose tissue. RBP4 release by white fat has been proposed to induce insulin resistance. We analyzed the regulation and production of RBP4 in brown adipose tissue. RBP4 gene expression is induced in brown fat from mice exposed to cold or treated with peroxisome proliferator-activated receptor (PPAR) agonists. In brown adipocytes in culture, norepinephrine, cAMP, and activators of PPARγ and PPARα induced RBP4 gene expression and RBP4 protein release. The induction of RBP4 gene expression by norepinephrine required intact PPAR-dependent pathways, as evidenced by impaired response of the RBP4 gene expression to norepinephrine in PPARα-null brown adipocytes or in the presence of inhibitors of PPARγ and PPARα. PPARγ and norepinephrine can also induce the RBP4 gene in white adipocytes, and overexpression of PPARα confers regulation by this PPAR subtype to white adipocytes. The RBP4 gene promoter transcription is activated by cAMP, PPARα, and PPARγ. This is mediated by a PPAR-responsive element capable of binding PPARα and PPARγ and required also for activation by cAMP. The induction of the RBP4 gene expression by norepinephrine in brown adipocytes is protein synthesis dependent and requires PPARγ-coactivator-1-α, which acts as a norepinephine-induced coactivator of PPAR on the RBP4 gene. We conclude that PPARγ- and PPARα-mediated signaling controls RBP4 gene expression and releases in brown adipose tissue, and thermogenic activation induces RBP4 gene expression in brown fat through mechanisms involving PPARγ-coactivator-1-α coactivation of PPAR signaling.

scholarly journals Eicosapentaenoic acid regulates brown adipose tissue metabolism in high-fat-fed mice and in clonal brown adipocytes

2017 ◽  
Vol 39 ◽  
pp. 101-109 ◽  
Author(s):  
Mandana Pahlavani ◽  
Fitia Razafimanjato ◽  
Latha Ramalingam ◽  
Nishan S. Kalupahana ◽  
Hanna Moussa ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Eicosapentaenoic Acid ◽  
Brown Adipose Tissue ◽  
High Fat ◽  
Brown Adipocytes ◽  
Adipose Tissue Metabolism ◽  
Tissue Metabolism ◽  
Brown Adipose

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)

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