Lactational metformin exposure programs offspring white adipose tissue glucose homeostasis and resilience to metabolic stress in a sex-dependent manner

• Published in: American journal of physiology: endocrinology and metabolism Vol. 318; no. 5; pp. E600 - E612
• Main Authors: Carlson, Zach, Hafner, Hannah, Mulcahy, Molly, Bullock, Kaylie, Zhu, Allen, Bridges, Dave, Bernal-Mizrachi, Ernesto, Gregg, Brigid
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2020
• Subjects: Adipocytes; Adipose tissue; Adipose Tissue, White - drug effects; Adipose Tissue, White - metabolism; Animals; Antidiabetics; Beta cells; Biomedical materials; Birth; Body fat; Breastfeeding & lactation; Cell proliferation; Cell Proliferation - drug effects; Exposure; Female; Gestation; Glucose; Glucose - metabolism; Glucose tolerance; Homeostasis; Homeostasis - drug effects; Hypoglycemic Agents - pharmacology; In vivo methods and tests; Insulin; Insulin secretion; Lactation; Male; Maternal Exposure; Metabolism; Metformin; Metformin - pharmacology; Mice; Morphology; Necropsy; Offspring; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects - metabolism; Sex Factors; Stress, Physiological - drug effects; Stress, Physiological - physiology; Young adults; neonatal; metformin; adipose; lactation; developmental programming
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00473.2019

We previously demonstrated that exposing mouse dams to metformin during gestation results in increased beta-cell mass at birth and increased beta-cell insulin secretion in adult male offspring. Given these favorable changes after a gestational maternal metformin exposure, we wanted to understand the long-term metabolic impact on offspring after exposing dams to metformin during the postnatal window. The newborn period provides a feasible clinical window for intervention and is important for beta-cell proliferation and metabolic tissue development. Using a C57BL/6 model, we administered metformin to dams from the day of birth to postnatal . We monitored maternal health and offspring growth during the lactation window, as well as adult glucose homeostasis through in vivo testing. At necropsy we assessed pancreas and adipocyte morphology using histological and immunofluorescent staining techniques. We found that metformin exposure programmed male and female offspring to be leaner with a higher proportion of small adipocytes in the gonadal white adipose tissue (GWAT). Male, but not female, offspring had an improvement in glucose tolerance as young adults concordant with a mild increase in insulin secretion in response to glucose in vivo. These data demonstrate long-term metabolic programming of offspring associated with maternal exposure to metformin during lactation.