Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice

Abstract

Pit1 null (Snell dwarf) and Proph1 null (Ames dwarf) mutant mice lack GH, PRL and TSH. Snell and Ames dwarf mice also exhibit reduced IGF-I, resistance to cancer and a longer lifespan than control mice. Endogenous glucose production during fasting is reduced in Snell dwarf mice compared to fasting control mice. In view of cancer cell dependence on glucose for energy, low endogenous glucose production may provide Snell dwarf mice with resistance to cancer. We investigated whether endogenous glucose production is lower in Snell dwarf mice during feeding. Inhibition of endogenous glucose production by glucose injection was enhanced in 12 to 14 month-old female Snell dwarf mice. Thus, we hypothesize that lower endogenous glucose production during feeding and fasting reduces cancer cell glucose utilization providing Snell dwarf mice with resistance to cancer. The elevation of circulating adiponectin, a hormone produced by adipose tissue, may contribute to the suppression of endogenous glucose production in 12 to 14 month-old Snell dwarf mice. We compared the incidence of cancer at time of death between old Snell dwarf and control mice. Only 18% of old Snell dwarf mice had malignant lesions at the time of death compared to 82% of control mice. The median ages at death for old Snell dwarf and control mice were 33 and 26 months, respectively. By contrast, previous studies showed a high incidence of cancer in old Ames dwarf mice at the time of death. Hence, resistance to cancer in old Snell dwarf mice may be mediated by neuroendocrine factors that reduce glucose utilization besides elevated adiponectin, reduced IGF-I and a lack of GH, PRL and TSH, seen in both Snell and Ames dwarf mice. Proteomics analysis of pituitary secretions from Snell dwarf mice confirmed the absence of GH and PRL, the secretion of ACTH and elevated secretion of Chromogranin B and Secretogranin II. Radioimmune assays confirmed that circulating Chromogranin B and Secretogranin II were elevated in 12 to 14 month-old Snell dwarf mice. In summary, our results in Snell dwarf mice suggest that the pituitary gland and adipose tissue are part of a neuroendocrine loop that lowers the risk of cancer during aging by reducing the availability of glucose.

Fig. 1

Endogenous glucose in 12 to 14 month-old female Snell dwarf mice after glucose injection. Control and Snell dwarf mice were injected with glucose (0.8 mg/g body weight) mixed with trace amounts of [³H]glucose (3 × 10⁵ cpm/mg glucose). Compared to control mice, plasma glucose was reduced in Snell dwarf mice at 2.5 5, 10, 15, 20 and 30 min after injection, indicating elevated glucose tolerance. Endogenous glucose in plasma was also reduced in Snell dwarf mice at 2.5, 5, 10, 15, 20 and 30 min after injection, indicating greater inhibition of endogenous glucose production. Results are shown as means ± SEM. *, **Significantly different at indicated time-points by nonparametric Student t-test between Snell dwarf and control mice where p < 0.05 and N = 6 mice per group.

Fig. 2

Percentage of old female Snell dwarf mice with neoplastic lesions at time of death. The percentage of mice with one or more neoplastic lesion at time of death was lower for Snell dwarf than control mice. The median age at time of death was 26 months for control and 33 months for Snell dwarf mice. Neoplastic lesions identified by histology included histiocytic sarcoma, lymphoma, mammary adenocarcinoma, fibrosarcoma, hepatocellular carcinoma, leiomyosarcoma, myelogenous leukemia and hemangiosarcoma. Bar graphs show results as means ± SEM. *Significantly different by χ² analysis where p < 0.05 and N = 33 control mice and N = 11 Snell dwarf mice.

Fig. 3

Circulating adiponectin in 12 to 14 month-old female Snell dwarf mice. Plasma adiponectin was elevated in Snell dwarf mice by Western blot analysis. Bar graphs show results as means ± SEM. *Significantly different by nonparametric Student t-test where p < 0.05 and N = 6 mice per group.

Fig. 4

(A) Circulating Chromogranin A, Chromogranin B and Secretogranin II in 12 to 14 month-old female Snell dwarf mice. Plasma Chromogranin B and Secretogranin II were elevated in Snell dwarf mice by radioimmune assay. Bar graphs show results as means ± SEM. *Significantly different by nonparametric Student t-test where p < 0.05 and N = 15 mice per group for Chromogranin A and N = 5 mice per group for Chromogranin B and Secretogranin II. (B) Tissue Chromogranin B and Secretogranin II mRNA expression by Northern blot analysis in wild-type mice. Chromogranin B mRNA expression was detected in the pituitary and the adrenal glands while Secretogranin II mRNA expression was detected ubiquitously.

Fig. 5

Neuroendocrine inhibition of endogenous glucose production and resistance to cancer. Snell dwarf mice show elevated adiponectin, Chromogranin B and Secretogranin II and low endogenous glucose production. Furthermore, Snell dwarf mice are highly resistant to cancer. Adiponectin, Chromogranin B and Secretogranin II are shown as part of a complex neuroendocrine axis that can ultimately provide resistance to cancer.