Muscle uncoupling protein 3 expression is unchanged by chronic ephedrine/caffeine treatment: results of a double blind, randomised clinical trial in morbidly obese females.

Renata Bracale,Giovanni Scapagnini,Maria Letizia Petroni,Sergio Davinelli,Enzo Nisoli,Umberto Bracale,Michele O Carruba,Stephen L Atkin

doi:10.1371/journal.pone.0098244

Abstract

Ephedrine/caffeine combination (EC) has been shown to induce a small-to-moderate weight loss in obese patients. Several mechanisms have been proposed, among which an increased thermogenic capacity of skeletal muscle consequent to the EC-induced up-regulation of uncoupling protein 3 (UCP3) gene expression. We did a parallel group double-blind, placebo-controlled, 4-week trial to investigate this hypothesis. Thirteen morbidly obese women (25–52 years of age, body-mass index 48.0±4.0 kg/m2, range 41.1–57.6) were randomly assigned to EC (200/20 mg, n = 6) or to placebo (n = 7) administered three times a day orally, before undergoing bariatric surgery. All individuals had an energy-deficit diet equal to about 70% of resting metabolic rate (RMR) diet (mean 5769±1105 kJ/day). The RMR analysed by intention to treat and the UCP3 (long and short isoform) mRNA levels in rectus abdominis were the primary outcomes. Body weight, plasma levels of adrenaline, noradrenaline, triglycerides, free fatty acids, glycerol, TSH, fT4, and fT3 were assessed, as well as fasting glucose, insulin and HOMA index, at baseline and at the end of treatments. Body weight loss was evident in both groups when compared to baseline values (overall −5.2±3.2%, p<0.0001) without significant differences between the treated groups. EC treatment increased the RMR (+9.2±6.8%, p = 0.020), differently from placebo which was linked to a reduction of RMR (−7.6±6.5%, p = 0.029). No significant differences were seen in other metabolic parameters. Notably, no changes of either UCP3 short or UCP3 long isoform mRNA levels were evident between EC and placebo group. Our study provides evidence that 4-week EC administration resulted in a pronounced thermogenic effect not related to muscle UCP3 gene expression and weight loss in morbidly obese females under controlled conditions.Trial RegistrationClinicalTrials.gov NCT02048215

Highlights

Ephedrine and caffeine (EC) combination has been widely used in human obesity treatment [1,2], and is still present in many herbal preparations sold widespread in many countries for weight loss
We studied 13 morbidly obese females, 36.3610.3 year-old with body mass index (BMI) by 48.064.0 kg/m2
Because only a few small studies have been done in humans to investigate the thermogenic effects of EC, in the present study we examined the uncoupling protein 3 (UCP3) expression in skeletal muscle of premenopausal morbidly obese females treated with either placebo or EC for 28 days

Summary

Introduction

Ephedrine and caffeine (EC) combination has been widely used in human obesity treatment [1,2], and is still present in many herbal preparations sold widespread in many countries for weight loss. Ephedrine is an agonist of both aand b-adrenoceptors; it induces noradrenaline release from sympathetic neurons, and it is a sympatho-mimetic drug with a mixed profile [5]. Caffeine increases both noradrenaline and dopamine release and stimulates the neuronal activity in several brain regions. Caffeine antagonizes the inhibitory effects of adenosine on sympathetic nervous system (SNS). This modulation of SNS activity may be a possible explanation for the thermic effect of EC [6,7]. The physiological role of UCP1 is to uncouple oxidative phosphorylation, most of the energy is dissipated as heat rather than being converted to ATP [9]

Methods

Results

Conclusion