Obesity impairs lactation performance in mice by inducing prolactin resistance

Abstract

Obesity reduces breastfeeding success and lactation performance in women. However, the mechanisms involved are not entirely understood. In the present study, female C57BL/6 mice were chronically exposed to a high-fat diet to induce obesity and subsequently exhibited impaired offspring viability (only 15% survival rate), milk production (33% reduction), mammopoiesis (one-third of the glandular area compared to control animals) and postpartum maternal behaviors (higher latency to retrieving and grouping the pups). Reproductive experience attenuated these defects. Diet-induced obese mice exhibited high basal pSTAT5 levels in the mammary tissue and hypothalamus, and an acute prolactin stimulus was unable to further increase pSTAT5 levels above basal levels. In contrast, genetically obese leptin-deficient females showed normal prolactin responsiveness. Additionally, we identified the expression of leptin receptors specifically in basal/myoepithelial cells of the mouse mammary gland. Finally, high-fat diet females exhibited altered mRNA levels of ERBB4 and NRG1, suggesting that obesity may involve disturbances to mammary gland paracrine circuits that are critical in the control of luminal progenitor function and lactation. In summary, our findings indicate that high leptin levels are a possible cause of the peripheral and central prolactin resistance observed in obese mice which leads to impaired lactation performance.

Cafeteria Diet Consumption during Lactation in Rats, Rather than Obesity Per Se, alters miR‐222, miR‐200a, and miR‐26a Levels in Milk

“…Notably, biological functions regulated by prolactin signaling, such as milk production and other maternal behaviors, are impaired in obese females . Concretely, it has been postulated that high leptin levels are a possible cause of the peripheral and central prolactin resistance presented by obese animals, which leads to impaired lactation performance . However, in our models of cafeteria and postcafeteria, no differences were observed in these miRNAs (miR‐103 and miR‐27) modulated by prolactin during lactation in obese dams, probably because our animals are not leptin resistance, although they presented higher leptinemia.…”

“…Thus, changes observed here in miR‐103 and miR‐27 levels in milk during lactation could be mediated by prolactin, whose levels decrease once lactation is established . Notably, biological functions regulated by prolactin signaling, such as milk production and other maternal behaviors, are impaired in obese females . Concretely, it has been postulated that high leptin levels are a possible cause of the peripheral and central prolactin resistance presented by obese animals, which leads to impaired lactation performance .…”

Impaired prolactin actions mediate altered offspring metabolism induced by maternal high‐fat feeding during lactation

“…Long‐term obesity (before mating) is known to reduce lactation performance by inducing central and MG prolactin resistance (37, 38). However, it is unknown whether HFD feeding during lactation, independent of obesity, affects MG function and lactation efficiency.…”

“…In humans, obesity is associated with reduced breastfeeding success, delayed initiation of lactation, lower milk yield, and early cessation of breastfeeding (37, 38, 47, 48). Consistently, in rodents, an HFD before mating and throughout gestation and lactation results in altered MG morphology and function as well as reduced lactation performance (37, 41, 42).…”

Histological and Metabolic State of Dams Suckling Small Litter or MSG-Treated Pups

“…For example, obesogenic maternal diets, with an excess of nutrients, such as lipids or carbohydrates, can lead to changes in milk volume [3, 4] and milk composition, affecting lactose [5] and fat content [5, 6]. In this regard, mice that are chronically exposed to a high fat diet present a reduction in mammary gland (MG) area, high leptin levels, and systemic prolactin resistance, which lead to impaired lactation performance [7]. Moreover, maternal obesity or undernutrition, during lactation, affects offspring growth, predisposing them to the development of obesity and cardiovascular disease in adult life [8, 9].…”