High Fat Diet-Induced Loss of Pituitary Plasticity in Aging Female Mice with Ablated Leptin Signaling in Somatotropes

Tiffany K Miles^*Angela K. OdleStephanie D. ByrumAlex N. LagasseAnessa C. HaneyVictoria G. OrtegaAshley K. HerdmanMelanie C. MacNicolAngus M. MacNicolGwen V. Childs^*

• Neuroscience, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States

This study examined how a high-fat diet (HFD) affected pituitary function in older (10-month) female mutants lacking leptin receptors (LEPR) in somatotropes and intact littermate controls. Somatotrope LEPR-null mutants on a HFD gained only 75% of the weight of controls and were more glucose tolerant, which may be attributed to the finding that they consumed less food, were more active, and had lower serum levels of insulin. In both mutants and controls, the HFD decreased serum levels of growth hormone (GH) and prolactin (PRL); however, in controls but not mutants, it elevated adrenocorticotropin (ACTH) levels. Additionally, the HFD resulted in elevated serum leptin and higher serum IL-6 in both mutants and controls. Analysis of single-cell RNA transcriptomics of control and mutant female pituitaries revealed that the HFD induced differentially expressed genes (DEGs) in more distinct pituitary cell populations compared to previously reported findings in younger control females, indicating greater vulnerability in the older pituitary population. Ingenuity Pathway Analysis indicated that the DEGs included targets of critical upstream regulators important for pituitary cell function and plasticity, encompassing the CREB, Fox01, cAMP, STAT3, insulin, TRH, GnRH, and leptin signaling pathways, with most pathways predicted to be downregulated by the HFD. Unlike controls, HFD-fed mutant cell populations exhibited DEGs consistent with the downregulation of translational regulatory pathways. Notably, the HFD also reversed the increased expression of progenitor cell markers (Sox9+) and multiple pituitary hormone transcripts-(Pomc, Prl, Lhb, Tshb and Cga) seen in the mutant somatotropes, which we reported previously was induced by the reduced leptin signaling. Similarly, the HFD reversed the expression of multiple pituitary hormone transcripts and progenitor markers in lactotropes, thyrotropes, and corticotropes from mutants. Collectively, these findings indicate that HFD and/or obese state may compromise pituitary plasticity by reducing cells that may have multipotential functions, limiting the expression of pituitary progenitor cells.