Serotonin Deficiency Rescues Lactation on Day 1 in Mice Fed a High Fat Diet

Abstract

Obesity is an inflammatory state associated with delayed lactogenesis stage II and altered mammary gland morphology. Serotonin mediates inflammation and mammary gland involution. The objective of this study was to determine if a genetic deficiency of tryptophan hydroxylase 1, the rate-limiting enzyme in peripheral serotonin synthesis, would result in an improved ability to lactate in dams fed a high fat diet. Twenty-six female mice were fed a high (HFD) or low fat (LFD) diet throughout pregnancy and lactation. Fourteen mice were genetically deficient for Tph1 (Tph1-/-), and twelve were wild type. Milk yield, pup mortality, and dam weights were recorded and milk samples were collected. On day 10 of lactation, dams were sacrificed and mammary glands were harvested for RT-PCR and histological evaluation. HFD dams weighed more than LFD dams at the onset of lactation. WT HFD dams were unable to lactate on day 1 of lactation and exhibited increased pup mortality relative to all other treatments, including Tph1-/- HFD dams. mRNA expression of immune markers C-X-C motif chemokine 5 and tumor necrosis factor alpha were elevated in WT HFD mammary glands. Mammary gland histology showed a reduced number of alveoli in WT compared to Tph1-/- dams, regardless of diet, and the alveoli of HFD dams were smaller than those of LFD dams. Finally, fatty acid profile in milk was dynamic in both early and peak lactation, with reduced de novo synthesis of fatty acids on day 10 of lactation in the HFD groups. Administration of a HFD to C57BL/6 dams produced an obese phenotype in the mammary gland, which was alleviated by a genetic deficiency of Tph1. Serotonin may modulate the effects of obesity on the mammary gland, potentially contributing to the delayed onset of lactogenesis seen in obese women.

Mammary gland adipocytes in lactation cycle, obesity and breast cancer

“…Consistently to what observed in genetic models, diet induced obese mice exhibit lower pregnancy success, higher stillbirth rate and impaired lactogenesis during the first post-natal days compared to regularly fed mice [31,62]. The impaired lactogenesis was ascribed to the abnormal side-ductal branching and altered alveolar development at pregnancy day 14 th [31] and was associated with reduced pups' body weight [31,62] and increased mortality [62]. Kamikawa and colleagues revealed the presence of reduced ductal branching frequency and altered ductal layers due to incomplete myoepithelial lining in the MG of high fat diet fed mice as compared to normofed controls (Fig.…”

Characterization of mammary-specific disruptions for Tph1 and Lrp5 during murine lactation

“…Despite slight histological differences, data from the present study demonstrate that the ability to produce milk and support pups was not affected by mammary-specific manipulation of the serotonergic system. Elevated concentrations of serotonin stimulate involution 9 and disruption of Tph1 rescued milk synthesis in the HFD-fed mammary gland 19 . As such, while elevated serotonin activity may negatively affect milk yield, our data suggests that the mammary gland has compensatory mechanisms to assure proper milk synthesis in the absence of serotonin.…”

“…For example, serotonin modulates calcium homeostasis in rodents 14 , 15 , and both late lactation 16 and transition period 17 in dairy cows. In addition, serotonin affects mammary gland function following administration of a high fat diet in various rodent models 18 , 19 , and breast-to-bone communication 20 . Recently, a relationship has been suggested between the serotonergic and circadian systems in regulating mammary gland development and function 21 .…”

Effect of high-fat diet feeding and associated transcriptome changes in the peak lactation mammary gland in C57BL/6 dams

“…Milk yield. Milk yield data were recorded from L1 to L9 by previously published methods (61). In brief, pups were separated from their mothers at~8:00 AM starting from L1.…”