Insulin, a key regulator of hormone responsive milk protein synthesis during lactogenesis in murine mammary explants

Abstract

Murine milk protein gene expression requires insulin, hydrocortisone, and prolactin; however, the role of insulin is not well understood. This study, therefore, examined the requirement of insulin for milk protein synthesis. Mammary explants were cultured in various combinations of the lactogenic hormones and global changes in gene expression analysed using Affymetrix microarray. The expression of 164 genes was responsive to insulin, and 18 were involved in protein synthesis at the level of transcription and posttranscription, as well as amino acid uptake and metabolism. The folate receptor gene was increased by fivefold, highlighting a potentially important role for the hormone in folate metabolism, a process that is emerging to be central for protein synthesis. Interestingly, gene expression of two milk protein transcription factors, Stat5a and Elf5, previously identified as key components of prolactin signalling, both showed an essential requirement for insulin. Subsequent experiments in HCll cells confirmed that Stat5a and Elf5 gene expression could be induced in the absence of prolactin but in the presence of insulin. Whereas prolactin plays an essential role in phosphorylating and activating Stat5a, gene expression is only induced when insulin is present. This indicates insulin plays a crucial role in the transcription of the milk protein genes.

Milk Protein Synthesis in the Lactating Mammary Gland: Insights from Transcriptomics Analyses

“…However, the pattern of insulinemia during lactation [37] appears to follow the pattern of milk protein concentration [4]. Recently, insulin has been demonstrated to play a key role in milk protein synthesis both in mice [38] and dairy cows [39]. Our own studies also support a pivotal role of insulin in milk protein synthesis [4].…”

“…For the former, it is well-known that insulin has a strong positive role in activation of STAT5 through increase phosphorylation of the transcription factor [151]. In addition, expression of ELF5, the gene coding for a co-activator and amplifier of STAT5 signaling (see above), is induced by insulin in cattle and mouse mammary tissues [38,39]. Those are direct or indirect effects of insulin on control of milk protein expression through STAT5-ELF5.…”

“…Despite the decrease of insulin, a role of this hormone in synthesis of the main milk constituents, particularly protein and lactose, in the bovine mammary gland was proposed more than 40 years ago [35]. Recent work has demonstrated a pivotal role of insulin in regulating milk protein synthesis both in the cow [39] and mouse [38].…”

Post-natal imprinting: evidence from marsupials

“…In mammals, insulin, in addition to cortisol and prolactin, is an absolute requirement for synthesis of milk (Menzies et al, 2010). In the tammar, insulin is a crucial requirement to stimulate milk-protein synthesis and establish lactation (Nicholas et al, 1991;Trott et al, 2002Trott et al, , 2005.…”

Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

“…The use of large transcriptomic analysis (i.e., microarray or RNA sequencing) by which to study the adaptation of mammary gland to lactation and/or change in milk production under specific conditions has been carried out in mouse (4,54,122,123,143,189,191,217,236,256), rat (3,47,187), bovine (31,36,56,75,96,144,183,209,218,233,239), sheep (209), goat (71,163,164), human (121,139,147), pig (204), kangaroo (120), and seal (144). It is beyond the scope of the current review to present a thorough discussion of the results from those studies.…”