(1110) Metformin Inhibits Insulin-induced Mammary Lipid Synthesis: Development of Personalized Human Milk to Prevent Childhood Obesity

Infants born to obese mothers are at increased risk of childhood obesity due to in-utero programming and accelerated infant weight gain. The increased fat/calorie content of milk of mothers with obesity suggests that the maternal metabolic milieu, including increased serum insulin,  alters breast lipid synthesis. We utilized a 3-D immortalized human mammary epithelial cell (MEC) culture to examine the effects of exogenous insulin on lipid synthesis. We further hypothesized that Metformin would prevent insulin-induced milk lipid synthesis.

Study Design:

MECs were cultured on cell inserts which separate the basolateral chamber containing “serum” from the apical chamber of milk production. Insulin (5 ng/ml), with and without Metformin (5 µmol/L), was added to the lactogenic medium within the basolateral chamber. After 48h, MECs were analyzed for protein expression (Western Blot) of lipogenic transcription factor (sterol regulatory element-binding protein, SREBP), and enzymes involved in triglyceride uptake (lipoprotein lipase, LPL) and fatty acid synthesis (fatty acid synthase, FAS). Treated vs. untreated MECs were compared by ANOVA with Dunnett’s post-hoc test. Values are fold change (mean ± SEM) of N=4 independent cultures.

Results: In response to insulin, cellular MECs demonstrated activation of the lipid synthesis pathway as evident by increased protein expression of SREBP1 including its downstream target enzymes LPL and FAS. Metformin treatment normalized the insulin-induced upregulation of MEC lipid synthesis (Fig 1).

Conclusion: The increased fat/caloric content of milk of obese mothers is a result, in part, of insulin-enhanced mammary lipid synthesis. Consistent with hepatic effects, Metformin reduces insulin-mediated lipogenesis. These findings suggest that excess human milk lipid synthesis may be normalized by maternal diet or pharmacologic interventions which reduce serum insulin. The extension of personalized human milk from the low birth weight to macrosomic infants may prevent excess infant weight gain resulting from high caloric breast milk.