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

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.

Serum Secretogranin III Concentrations Were Increased in Subjects with Metabolic Syndrome and Independently Associated with Fasting Plasma Glucose Levels

“…Notably, the SCG3-CPE interaction helps this prohormone processing [17]. In line with this concept, previous studies indicated that SCG3 had some roles in assisting the formation of insulin-containing secretory granules and insulin processing, thus affecting glucose homeostasis [18,19]. In our study, serum SCG3 concentrations were positively related to FPG, glycated hemoglobin, and glucose levels at two hours of the OGTT.…”

“…Acting as a bridge of peptides and a trans-Golgi network, it sorts these prohormones into secretory granules [16,17]. As for insulin secretion, SCG3 also had some roles in assisting insulin processing, thus affecting glucose homeostasis [18,19]. It has been shown that significantly increased SCG3 levels were detected in serum-free media conditioned with non-responsive high-passage MIN-6 cells, a model of dysfunctional beta cells.…”

“…These data implied that secretory granules can no longer form properly, thus decreasing the insulin-secreting ability of beta cells, when SCG3 was massively released from, but did not remain inside, those cells [18]. Additionally, proinsulin was found to be insufficiently converted into the mature form, insulin, in islet cells, thus leading to hyperglycemia, in SCG3-knockout mice fed a high-fat/high-sucrose diet [19]. This finding suggests the role of SCG3 in proteolytic conversion of the inactive prohormone to the active hormone [19].…”

“…Additionally, proinsulin was found to be insufficiently converted into the mature form, insulin, in islet cells, thus leading to hyperglycemia, in SCG3-knockout mice fed a high-fat/high-sucrose diet [19]. This finding suggests the role of SCG3 in proteolytic conversion of the inactive prohormone to the active hormone [19]. Taking those results together, SCG3 may be involved in glucose homeostasis by regulating insulin processing and secretions by pancreatic beta cells.…”

The Latest Insights into Adipokines in Diabetes

“…SCG3 is a member of the granin family found in various endocrine and neuroendocrine cells [29,30,31]. It affects glucose homeostasis by regulating insulin secretion from pancreatic β-cells [32,33]. MetS is characterized by compensatory hyperinsulinemia and insulin resistance [34,35].…”