Metformin Prevents Key Mechanisms of Obesity-Related Complications in Visceral White Adipose Tissue of Obese Pregnant Mice

Abstract

With the gaining prevalence of obesity, related risks during pregnancy are rising. Inflammation and oxidative stress are considered key mechanisms arising in white adipose tissue (WAT) sparking obesity-associated complications and diseases. The established anti-diabetic drug metformin reduces both on a systemic level, but only little is known about such effects on WAT. Because inhibiting these mechanisms in WAT might prevent obesity-related adverse effects, we investigated metformin treatment during pregnancy using a mouse model of diet-induced maternal obesity. After mating, obese mice were randomised to metformin administration. On gestational day G15.5, phenotypic data were collected and perigonadal WAT (pgWAT) morphology and proteome were examined. Metformin treatment reduced weight gain and visceral fat accumulation. We detected downregulation of perilipin-1 as a correlate and observed indications of recovering respiratory capacity and adipocyte metabolism under metformin treatment. By regulating four newly discovered potential adipokines (alpha-1 antitrypsin, Apoa4, Lrg1 and Selenbp1), metformin could mediate anti-diabetic, anti-inflammatory and oxidative stress-modulating effects on local and systemic levels. Our study provides an insight into obesity-specific proteome alterations and shows novel modulating effects of metformin in pgWAT of obese dams. Accordingly, metformin therapy appears suitable to prevent some of obesity’s key mechanisms in WAT.

Profound perturbations are found in the proteome and metabolome in children with obesity after weight loss intervention

“…For instance, the levels of lecithin cholesterol acyltransferase (LCAT), which is a crucial enzyme for HDL metabolism [ 23 , 24 ], are significantly increased, mirroring IR and diet-induced obesity [ 25 ]. The levels of MYH10 are increased in obese pregnant mice [ 26 ], and its interaction with insulin-dependent glucose transporter 4 (GLUT4) regulates adipocyte function and adipogenesis [ 27 ]. The findings of these studies are conceptually consistent with our results that the levels of MYH10 were significantly decreased in children with obesity who had undergone weight loss intervention and may play an important role in weight loss.…”

Lipids Alterations Associated with Metformin in Healthy Subjects: An Investigation Using Mass Spectrometry Shotgun Approach

“…Metformin therapy during gestation reduces weight gain and visceral white adipose tissue mass. It offers plenty of effects suitable for inhibiting obesity’s key mechanisms in visceral white adipose tissue, such as inflammation, oxidative stress, and tissue dysfunction [ 67 ]. A previous animal study found that metformin has a dual effect on the differentiation of 3T3-L1 preadipocyte cells by promoting or suppressing adipogenesis and that lower concentrations of metformin induce 3T3-L1 preadipocyte differentiation.…”