Metabolic alterations associated with the antidiabetic effect of beta 3-adrenergic receptor agonists in obese mice

Treatment of obese (ob/ob) mice with the beta 3-adrenergic receptor (beta 3-AR) agonist BRL-35135 (1 mg.kg body wt-1.day-1 for 20 days) normalized plasma glucose levels and significantly decreased plasma insulin and nonesterified fatty acid levels. The time frame for the hypoglycemic effect, which reached a maximum after 10 days of treatment, paralleled an increase in brown adipose tissue DNA and protein content. The basal level of mRNA for the beta 3-AR and mitochondrial uncoupling protein was found to be markedly decreased in the ob/ob animals relative to the lean group. Chronic treatment of ob/ob mice for 20 days resulted in a twofold increase in beta 3-AR mRNA and a fivefold increase in uncoupling protein mRNA in brown adipose tissue relative to the placebo group. These findings indicate that chronic treatment of ob/ob animals with a beta 3-AR agonist results in proliferation of brown adipose tissue, with an upregulation of the beta 3-AR, which is associated with a decrease in plasma glucose, insulin, and nonesterified fatty acid levels.

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Characterization and regulation of cold-induced heat shock protein expression in mouse brown adipose tissue

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1995.269.1.r38 ◽

1995 ◽

Vol 269 (1) ◽

pp. R38-R47 ◽

Cited By ~ 15

Author(s):

J. M. Matz ◽

M. J. Blake ◽

H. M. Tatelman ◽

K. P. Lavoi ◽

N. J. Holbrook

Keyword(s):

Adipose Tissue ◽

Heat Shock ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

Elevated Temperatures ◽

Uncoupling Protein ◽

Hsp70 Expression ◽

Mitochondrial Uncoupling ◽

Ambient Temperatures ◽

Brown Adipose

The accumulation of heat shock proteins (HSPs) after the exposure of cells or organisms to elevated temperatures is well established. It is also known that a variety of other environmental and cellular metabolic stressors can induce HSP synthesis. However, few studies have investigated the effect of cold temperature on HSP expression. Here we report that exposure of Institute of Cancer Research (ICR) mice to cold ambient temperatures results in a tissue-selective induction of HSPs in brown adipose tissue (BAT) coincident with the induction of mitochondrial uncoupling protein synthesis. Cold-induced HSP expression is associated with enhanced binding of heat shock transcription factors to DNA, similar to that which occurs after exposure of cells or tissues to heat and other metabolic stresses. Adrenergic receptor antagonists were found to block cold-induced HSP70 expression in BAT, whereas adrenergic agonists induced BAT HSP expression in the absence of cold exposure. These findings suggest that norepinephrine, released in response to cold exposure, induces HSP expression in BAT. Norepinephrine appears to initiate transcription of HSP genes after binding to BAT adrenergic receptors through, as yet, undetermined signal transduction pathways. Thermogenesis results from an increase in activity and synthesis of several metabolic enzymes in BAT of animals exposed to cold challenge. The concomitant increase in HSPs may function to facilitate the translocation and activity of the enzymes involved in this process.

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Thyroxine 5'-deiodinase in brown adipose tissue of myopathic hamsters

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1986.251.1.e8 ◽

1986 ◽

Vol 251 (1) ◽

pp. E8-E13 ◽

Cited By ~ 1

Author(s):

J. Kopecky ◽

L. Sigurdson ◽

I. R. Park ◽

J. Himms-Hagen

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

Uncoupling Protein ◽

High Fat ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

Endogenous Production ◽

Deiodinase Activity ◽

Brown Adipose

Myopathic Syrian hamsters (BIO 14.6) have less brown adipose tissue (BAT) than normal. The trophic response of this tissue to cold is smaller than normal and trophic responses to diet and to photoperiod are absent. The objective was to find out whether activity of thyroxine 5'-deiodinase in their BAT was increased normally in response to cold and thus whether a defect in endogenous production of 3,5,3'-triiodothyronine might underlie the attenuated trophic response. The effect of feeding a high-fat diet on activity of 5'-deiodinase was also studied. Cold acclimation increased thyroxine 5'-deiodinase activity in BAT of the myopathic hamster, but the total remained smaller than normal because of the smaller size. The cold-induced increase in concentration of mitochondrial uncoupling protein was also smaller than normal. The level of serum 3,5,3'-triiodothyronine was low in myopathic hamsters and remained lower than normal when they were cold-exposed or cold acclimated. Feeding the high-fat diet to myopathic hamsters resulted in a greater than normal suppression of thyroxine 5'-deiodinase activity than in normal hamsters; the normal increases in protein content and in concentration of mitochondrial uncoupling protein were absent. We conclude that the defective trophic response of BAT of the myopathic hamster is not secondary to defective regulation of its thyroxine 5'-deiodinase activity because this activity does not appear to be obligatorily linked to hypertrophy of BAT. The low level of serum 3,5,3'-triiodothyronine in the myopathic hamster may be secondary to reduced capacity for peripheral thyroxine deiodination in its BAT.

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The possible proton translocating activity of the mitochondrial uncoupling protein of brown adipose tissue

FEBS Letters ◽

10.1016/0014-5793(83)80300-7 ◽

1983 ◽

Vol 164 (2) ◽

pp. 272-276 ◽

Cited By ~ 15

Author(s):

F. Bouillaud ◽

D. Ricquier ◽

T. Gulik-Krzywicki ◽

C.M. Gary-Bobo

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

Brown Adipose

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Measurement by radioimmunoassay of the mitochondrial uncoupling protein from brown adipose tissue of obese (ob/ob) mice and Zucker (fa/fa) rats at different ages

FEBS Letters ◽

10.1016/0014-5793(85)80525-1 ◽

1985 ◽

Vol 179 (2) ◽

pp. 233-237 ◽

Cited By ~ 26

Author(s):

Margaret Ashwell ◽

Susan Holt ◽

Graham Jennings ◽

Dorothy M. Stirling ◽

Paul Trayhurn ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

Brown Adipose ◽

Different Ages

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Regulation of GDP binding and uncoupling-protein concentration in brown-adipose-tissue mitochondria. The effects of cold-acclimation, warm-reacclimation and noradrenaline

Biochemical Journal ◽

10.1042/bj2490451 ◽

1988 ◽

Vol 249 (2) ◽

pp. 451-457 ◽

Cited By ~ 27

Author(s):

T Peachey ◽

R R French ◽

D A York

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Protein Concentration ◽

Uncoupling Protein ◽

Potassium Acetate ◽

Zucker Rats ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

Acute Response ◽

Brown Adipose

We have used a specific immunoassay for uncoupling protein and [3H]GDP binding to study the acute and chronic responses of brown-adipose-tissue (BAT) mitochondria of warm-acclimated rats to housing at 4 degrees C and cold-acclimated rats to housing at 27 degrees C. These studies have shown the following. (1) In the cold-exposed rat the increase in mitochondrial uncoupling-protein concentration parallels the increase in GDP binding from 1 day to 5 days, but that acutely (initial 4 h) the increase in GDP binding is not associated with any change in uncoupling-protein concentration. 2. In the cold-acclimated rat rehoused at 27 degrees C, GDP binding fell by over 50% in the first 2 days, without any change in uncoupling-protein concentrations. 3. Noradrenaline acutely (30 min) increased BAT mitochondrial GDP binding of lean and obese Zucker rats, without any change in uncoupling-protein concentrations. 4. The increases in GDP binding in cold-exposed rats were associated with increases in the rate of swelling of mitochondria in the presence of valinomycin and potassium acetate. The evidence supports the hypothesis that the acute response of the rat to changes in environmental temperature are associated with unmasking or remasking of uncoupling protein, whereas chronically changes in uncoupling-protein concentration predominate.

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Immunochemical detection and quantitation of brown adipose tissue uncoupling protein

Biochemistry and Cell Biology ◽

10.1139/o87-032 ◽

1987 ◽

Vol 65 (3) ◽

pp. 245-251 ◽

Cited By ~ 9

Author(s):

Mary F. Henningfield ◽

Robert W. Swick

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Mammalian Species ◽

Sodium Dodecyl ◽

Mitochondrial Uncoupling ◽

Immunochemical Method ◽

Nucleotide Binding Sites ◽

Mitochondrial Uncoupling Protein ◽

Brown Adipose

A polyclonal antisera against rat brown adipose tissue mitochondrial uncoupling protein was used to examine mitochondrial samples from liver and white and brown adipose tissue from several mammalian species. A sodium dodecyl sulfate – polyacrylamide gel electrophoretic separation of proteins combined with an immunochemical method allowed for visualization of antigen–antibody complexes on nitrocellulose blots. Hamster, cavy, monkey, and mouse brown adipose tissue mitochondrial samples cross-reacted with the antisera. Mitochondria prepared from white fat obtained from young swine and sheep contained two closely migrating, antigenically active proteins. Hepatic mitochondria samples did not contain antigenically active protein. Reflectance densitometry was used for quantitation of the uncoupling protein in various mitochondrial samples. In rats fed diets low in protein, there appears to be a dissociation between the concentration of uncoupling protein and the number of nucleotide binding sites as given by the [3H]GDP binding assay. These results are indicative of a physiological activation of the uncoupling protein.

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Insulin selectively reduces mitochondrial uncoupling in brown adipose tissue in mice

Biochemical Journal ◽

10.1042/bcj20170736 ◽

2018 ◽

Vol 475 (3) ◽

pp. 561-569 ◽

Cited By ~ 11

Author(s):

Blake W. Dallon ◽

Brian A. Parker ◽

Aimee E. Hodson ◽

Trevor S. Tippetts ◽

Mitchell E. Harrison ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Mitochondrial Respiration ◽

Insulin Treatment ◽

Uncoupling Protein ◽

Mitochondrial Uncoupling ◽

Adipose Tissue Depots ◽

Brown Adipose ◽

A Site

The purpose of the present study was to determine the effects of prolonged hyperinsulinemia on mitochondrial respiration and uncoupling in distinct adipose tissue depots. Sixteen-week-old male mice were injected daily with placebo or insulin to induce an artificial hyperinsulinemia for 28 days. Following the treatment period, mitochondrial respiration and degree of uncoupling were determined in permeabilized perirenal, inguinal, and interscapular adipose tissue. White adipose tissue (WAT) mitochondria (inguinal and perirenal) respire at substantially lower rates compared with brown adipose tissue (BAT). Insulin treatment resulted in a significant reduction in mitochondrial respiration in inguinal WAT (iWAT) and interscapular BAT (iBAT), but not in perirenal WAT (pWAT). Furthermore, these changes were accompanied by an insulin-induced reduction in UCP-1 (uncoupling protein 1) and PGC-1α in iWAT and iBAT only, but not in pWAT or skeletal muscle. Compared with adipose tissue mitochondria in placebo conditions, adipose tissue from hyperinsulinemic mice manifested a site-specific reduction in mitochondrial respiration probably as a result of reduced uncoupling. These results may help explain weight gain so commonly seen with insulin treatment in type 2 diabetes mellitus.

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Mitochondrial uncoupling protein may participate in futile cycling of pyruvate and other monocarboxylates

AJP Cell Physiology ◽

10.1152/ajpcell.1998.275.2.c496 ◽

1998 ◽

Vol 275 (2) ◽

pp. C496-C504 ◽

Cited By ~ 26

Author(s):

Petr Jezek ◽

Jirí Borecky

Keyword(s):

Fatty Acids ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Specific Inhibitor ◽

Physiological Role ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

Brown Adipose ◽

Futile Cycling

The physiological role of monocarboxylate transport in brown adipose tissue mitochondria has been reevaluated. We studied pyruvate, α-ketoisovalerate, α-ketoisocaproate, and phenylpyruvate uniport via the uncoupling protein (UCP1) as a GDP-sensitive swelling in K+ salts induced by valinomycin or by monensin and carbonyl cyanide- p-(trifluoromethoxy)phenylhydrazone in Na+ salts. We have demonstrated that this uniport is inhibited by fatty acids. GDP inhibition in K+ salts was not abolished by an uncoupler, indicating a negligible monocarboxylic acid penetration via the lipid bilayer. In contrast, the electroneutral pyruvate uptake (swelling in ammonium pyruvate or potassium pyruvate induced by change in pH) mediated by the pyruvate carrier was inhibited by its specific inhibitor α-cyano-4-hydroxycinnamate but not by fatty acids. Moreover, α-cyano-4-hydroxycinnamate enhanced the energization of brown adipose tissue mitochondria, which was monitored fluorometrically by 2-(4-dimethylaminostyryl)-1-methylpyridinium iodide and safranin O. Consequently, we suggest that UCP1 might participate in futile cycling of unipolar ketocarboxylates under certain physiological conditions while expelling these anions from the matrix. The cycle is completed on their return via the pyruvate carrier in an H+ symport mode.

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