Impaired Processing of Prohormones in Secretogranin III–Null Mice Causes Maladaptation to an Inadequate Diet and Stress

• Published in: Endocrinology (Philadelphia) 2018-02, Vol.159 (2), p.1213-1227
• Main Authors: Maeda, Yoshinori, Kudo, Saki, Tsushima, Ken, Sato, Eri, Kubota, Chisato, Kayamori, Aika, Bochimoto, Hiroki, Koga, Daisuke, Torii, Seiji, Gomi, Hiroshi, Watanabe, Tsuyoshi, Hosaka, Masahiro
• Format: Article
• Language: English
• Subjects: Abnormalities; Adrenocorticotropic hormone; Biosynthesis; Cholesterol; Diet; Endocrinology; High fat diet; Hormones; Insulin; Menopause; Peptide hormones; Pituitary; Pituitary gland; Proopiomelanocortin; Proteolysis; Rodents; Secretion; Secretory vesicles; Storage; Stress; Sucrose; Sugar
• ISSN: 1945-7170; 0013-7227; 1945-7170
• DOI: 10.1210/en.2017-00636

Abstract Secretogranin III (SgIII), a member of the granin family, binds both to another granin, chromogranin A (CgA), and to a cholesterol-rich membrane that is destined for secretory granules (SGs). The knockdown of SgIII in adrenocorticotropic hormone (ACTH)–producing AtT-20 cells largely impairs the regulated secretion of CgA and ACTH. To clarify the physiological roles of SgIII in vivo, we analyzed hormone secretion and SG biogenesis in newly established SgIII-knockout (KO) mice. Although the SgIII-KO mice were viable and fertile and exhibited no overt abnormalities under ordinary rearing conditions, a high-fat/high-sucrose diet caused pronounced obesity in the mice. Furthermore, in the SgIII-KO mice compared with wild-type (WT) mice, the stimulated secretion of active insulin decreased substantially, whereas the storage of proinsulin increased in the islets. The plasma ACTH was also less elevated in the SgIII-KO mice than in the WT mice after chronic restraint stress, whereas the storage level of the precursor proopiomelanocortin in the pituitary gland was somewhat increased. These findings suggest that the lack of SgIII causes maladaptation of endocrine cells to an inadequate diet and stress by impairing the proteolytic conversion of prohormones in SGs, whereas SG biogenesis and the basal secretion of peptide hormones under ordinary conditions are ensured by the compensatory upregulation of other residual granins or factors. Knockout of secretogranin III reduced the spare capacity of endocrine cells to generate active hormones from their precursors, resulting in maladaptation of mice to an inadequate diet and stress.