Protective Effects of Individual and Combined Low Dose Beta-Carotene and Metformin Treatments against High-Fat Diet-Induced Responses in Mice

Abstract

Anti-obesity activity has been reported for beta-carotene (BC) supplementation at high doses and metformin (MET). We studied whether BC treatment at a closer to dietary dose and MET treatment at a lower than therapeutic dose are effective in ameliorating unwanted effects of an obesogenic diet and whether their combination is advantageous. Obesity-prone mice were challenged with a high-fat diet (HFD, 45% energy as fat) for 4 weeks while receiving a placebo or being treated orally with BC (3 mg/kg/day), MET (100 mg/kg/day), or their combination (BC+MET); a fifth group received a placebo and was kept on a normal-fat diet (10% energy as fat). HFD-induced increases in body weight gain and inguinal white adipose tissue (WAT) adipocyte size were attenuated maximally or selectively in the BC+MET group, in which a redistribution towards smaller adipocytes was noted. Cumulative energy intake was unaffected, yet results suggested increased systemic energy expenditure and brown adipose tissue activation in the treated groups. Unwanted effects of HFD on glucose control and insulin sensitivity were attenuated in the treated groups, especially BC and BC+MET, in which hepatic lipid content was also decreased. Transcriptional analyses suggested effects on skeletal muscle and WAT metabolism could contribute to better responses to the HFD, especially in the MET and BC+MET groups. The results support the benefits of the BC+MET cotreatment.

The combined effect of metformin and mirabegron on diet‐induced obesity

“…Some studies have reported that both Met and Mir can individually activate BAT thermogenesis, 27–29,39,40 while others have shown that only Mir but not Met promotes BAT thermogenesis 39,41,42 . Our study was consistent with the latter, finding that Mir but not Met enhanced BAT thermogenesis in both mouse models.…”

“…Furthermore, an increase in browning of WATs by Met/Mir treatment also contributed to this greater EE, leading to lower body adiposity in the treatment model. This was an intriguing finding given that Met alone did not significantly promote browning of scWAT in HFD‐fed mice in either treatment or prevention models, consistent with the literature 41 . In addition, Mir has been found to augment scWAT browning in chow‐fed 40 and DIO 31 mice, and it was also observed to increase WAT browning in humans with obesity 43,44 but interestingly, not in healthy individuals 28 .…”

“…This was an intriguing finding given that Met alone did not significantly promote browning of scWAT in HFD‐fed mice in either treatment or prevention models, consistent with the literature. 41 In addition, Mir has been found to augment scWAT browning in chow‐fed 40 and DIO 31 mice, and it was also observed to increase WAT browning in humans with obesity 43 , 44 but interestingly, not in healthy individuals. 28 It appears that Mir's thermogenic effects are dependent on adiposity or metabolic contexts, which may provide an explanation for our observation that Met/Mir did not produce an additive increase in scWAT browning in the prevention model, as there was not sufficient adiposity for Met/Mir to have an additive effect.…”

Lutein ameliorates high‐fat diet‐induced obesity, fatty liver, and glucose intolerance in C57BL/6J mice

“…A previous study reported that lutein supplementation up to 1,000 mg/kg/day is non‐toxic in mice models (Nidhi & Baskaran, 2013). The concentrations of lutein and orlistat were selected based on the reports of previous studies (Choi et al, 2016; Liu et al, 2017; Stojnić et al, 2021). The lutein concentration of 300 μM is equivalent to 1.5 mg/kg body weight and 500 μM is equivalent to 2.8 mg/kg body weight.…”

“…Since the dietinduced obesity model closely mimics the development of obesity in humans and is considered an essential tool for understanding the molecular mechanism (Collins, Martin, Surwit, & Robidoux, 2004;van der Klaauw & Sadaf Farooqi, 2015), we employed high-fat-fed (Nidhi & Baskaran, 2013). The concentrations of lutein and orlistat were selected based on the reports of previous studies (Choi et al, 2016;Liu et al, 2017;Stojni c et al, 2021). The lutein concentration of 300 μM is equivalent to 1.5 mg/kg body weight and 500 μM is equivalent to 2.8 mg/kg body weight.…”