Diazoxide enhances basal metabolic rate and fat oxidation in obese Zucker rats

Ramin Alemzadeh, Michael Karlstad, Kathryn Tushaus, Margaret Buchholz

Research output: Contribution to journalArticle

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Abstract

Persistent suppression of hyperinsulinemia in genetically obese (fa/fa) Zucker rats by diazoxide (DZ) reduces food intake and weight gain; improves insulin sensitivity, glycemic control, and lipid profile; and enhances β3-adrenergic function and lipolysis in adipose tissue. The aim of this study was to elucidate the effects of DZ on basal metabolic rate (BMR), fat oxidation, and adrenergic function of lean and obese Zucker rats. Diazoxide (150 mg/kg/d) or vehicle (control) was administered for 4 weeks in 7-week-old obese and lean Zucker rats (n = 8-9 per subgroup). Animals underwent indirect calorimetry, body composition analysis, and determination of uncoupling proteins (UCPs) messenger RNA (mRNA) in brown and white adipose tissues (BAT and WAT) and skeletal muscle (SM), β3-adrenergic receptor (AR) mRNA in BAT and WAT, β2-AR in SM as well as WAT, and SM adenylate cyclase (AC) activity at the completion of study. Diazoxide treatment decreased food intake, weight gain, and body fat in obese rats (P < .01). Although DZ treatment lowered fasting plasma glucose, insulin, leptin, adiponectin, and lipids in obese rats (P < .01), it increased adiponectin-leptin ratio (P < .01). Plasma adiponectin-leptin ratio was inversely correlated with fat mass in obese and lean rats (r = -0.86, P < .0001). Diazoxide treatment resulted in higher BMR and fat oxidation rate in obese compared with control animals (P < .01), without any effect in lean animals. Furthermore, plasma adiponectin was inversely correlated with BMR (-0.56, P < .001) and lipid oxidation rate (-0.61, P < .0005) and was positively correlated with nonprotein respiratory quotient (r = 0.41, P < .01) in obese and lean rats. This was associated with increased β3-AR mRNA expression in BAT and WAT (P < .01), UCP-1 and UCP-3 in BAT and AC activity in WAT (P < .02), and AC activity in SM of DZ obese rats compared with controls (P < .01), without significant change in SM β2-AR mRNA expressions. Diazoxide attenuation of hyperinsulinemia decreased the rate of weight gain but enhanced insulin sensitivity, BMR, and fat oxidation in obese rats. This was associated with increased receptor- and non-receptor-mediated adrenergic function in adipose and muscle tissues in obese rats, respectively. These metabolic changes in obese Zucker rats suggest that antiobesity effects of DZ appear to be not only through its anorectic effect, modification of disturbed insulin metabolism, and inhibition of lipogenesis, but also due to augmentation of adrenergic function, energy expenditure, and fat utilization.

Original languageEnglish (US)
Pages (from-to)1597-1607
Number of pages11
JournalMetabolism: clinical and experimental
Volume57
Issue number11
DOIs
StatePublished - Nov 1 2008

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Diazoxide
Zucker Rats
Basal Metabolism
Fats
Adiponectin
Skeletal Muscle
Adrenergic Agents
Adrenergic Receptors
Leptin
Adenylyl Cyclases
Weight Gain
Adipose Tissue
Messenger RNA
Hyperinsulinism
Lipids
Insulin Resistance
Eating
Insulin
Appetite Depressants
Indirect Calorimetry

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Diazoxide enhances basal metabolic rate and fat oxidation in obese Zucker rats. / Alemzadeh, Ramin; Karlstad, Michael; Tushaus, Kathryn; Buchholz, Margaret.

In: Metabolism: clinical and experimental, Vol. 57, No. 11, 01.11.2008, p. 1597-1607.

Research output: Contribution to journalArticle

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