Beneficial Effects of Alpha-Lipoic Acid on Hypertension, Visceral Obesity, UCP-1 Expression and Oxidative Stress in Zucker Diabetic Fatty Rats

Abstract

Evidence suggests that oxidative stress plays a major role in the development of metabolic syndrome. This study aims to investigate whether α-lipoic acid (LA), a potent antioxidant, could exert beneficial outcomes in Zucker diabetic fatty (ZDF) rats. Male 6-week-old ZDF rats and their lean counterparts (ZL) were fed for six weeks with a standard diet or a chow diet supplemented with LA (1 g/kg feed). At 12 weeks of age, ZDF rats exhibited an increase in systolic blood pressure, epididymal fat weight per body weight, hyperglycemia, hyperinsulinemia, insulin resistance (HOMA index), adipocyte hypertrophy and a rise in basal superoxide anion (O2•−) production in gastrocnemius muscle and a downregulation of epididymal uncoupled protein-1 (UCP-1) protein staining. Treatment with LA prevented the development of hypertension, the rise in whole body weight and O2•− production in gastrocnemius muscle, but failed to affect insulin resistance, hyperglycemia and hyperinsulinemia in ZDF rats. LA treatment resulted in a noticeable increase of pancreatic weight and a further adipocyte hypertrophy, along with a decrease in epididymal fat weight per body weight ratio associated with an upregulation of epididymal UCP-1 protein staining in ZDF rats. These findings suggest that LA was efficacious in preventing the development of hypertension, which could be related to its antioxidant properties. The anti-visceral obesity effect of LA appears to be mediated by its antioxidant properties and the induction of UCP-1 protein at the adipose tissue level in ZDF rats. Disorders of glucose metabolism appear, however, to be mediated by other unrelated mechanisms in this model of metabolic syndrome.

Effects of alpha lipoic acid on metabolic syndrome: A comprehensive review

“…MetS associated with obesity and can develop diabetes in some patients (McNeilly et al, 2011; Patel, Matnor, Iyer, & Brown, 2011). Likewise, other MetS conditions such as hypertension or dyslipidemia could be associated with diabetes status such as insulin resistance (El Midaoui, De Champlain, Sadi, Husain, & Fantus, 2007; El Midaoui, Fantus, Ait Boughrous, & Couture, 2019). Insulin resistance is considered a critical factor in the development of metabolic disorders (Yang et al, 2014).…”

Lipoic Acid Exacerbates Oxidative Stress and Lipid Accumulation in the Liver of Wistar Rats Fed a Hypercaloric Choline-Deficient Diet

“…It is believed that LA exerts anti-obesity effects by suppressing hypothalamic AMP-activated protein kinase activity followed by a reduction in food intake and an increase in energy expenditure [53,54]. Zucker diabetic fatty rats fed LA showed a decrease in epididymal fat weight per body weight ratio associated with an upregulation of epididymal uncoupled protein-1 that plays a key role in non-shivering thermogenesis [55].…”

Protective Effects of a Discontinuous Treatment with Alpha-Lipoic Acid in Obesity-Related Heart Failure with Preserved Ejection Fraction, in Rats

“…In this case the anti-obesity effect of ALA could be a consequence of the increase in energy expenditure, especially as ALA stimulates both cellular glucose uptake [60][61][62] and ATP synthesis, being an important cofactor of mitochondrial pyruvate and ketoglutarate dehydrogenases [63,64]. Furthermore, several studies have noted that ALA activates skeletal muscle 5' adenosine monophosphate-activated protein kinase (AMPK), with a subsequent enhancement of fatty acid β-oxidation [25,65] and increases mitochondrial uncoupling protein (UCP)-1 expression in adipose tissue, which has an important role in non-shivering thermogenesis [24]. Therefore, it could be assumed that by these two combined mechanisms, ALA increases whole-body energy expenditure [66], stimulating weight loss or preventing weight gain, depending on the initial body weight at the moment of treatment.…”

“…Moreover, its safety profile is well characterized [23] and its specific amphiphilic properties could allow for a better intra-cellular and extra-cellular distribution [22]. Consequently, multiple studies have reported the benefits of ALA treatment in metabolic syndrome (hyperglycemia, tissue insulin resistance and dyslipidemia) [17], hypertension [17,24] and obesity [25][26][27].…”