Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice.
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.
Alderman
J McKee
JM
University of North Carolina, Chapel Hill, NC 27599, USA.
Flurkey
Kevin
K
Brooks
Natasha L
NL
Naik
Sneha B
SB
Gutierrez
Jonathan M
JM
Srinivas
Urmila
U
Ziara
Kristen B
KB
Jing
Linhong
L
Boysen
Gunnar
G
Bronson
Rod
R
Klebanov
Simon
S
Chen
Xian
X
Swenberg
James A
JA
Stridsberg
Mats
M
Parker
Carol E
CE
Harrison
David E
DE
Combs
Terry P
TP
D000324:Adrenocorticotropic Hormone / Q000032:analysis / Q000378:metabolism; D000818:Animals; D053378:Chromogranin B / Q000097:blood / Q000378:metabolism; D004393:Dwarfism, Pituitary / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D013006:Growth Hormone / Q000172:deficiency; D007113:Immunity, Innate; D007334:Insulin-Like Growth Factor I / Q000172:deficiency; D008136:Longevity; D051379:Mice; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism*; D011388:Prolactin / Q000172:deficiency; D053381:Secretogranin II / Q000097:blood / Q000378:metabolism; D013972:Thyrotropin / Q000172:deficiency
D053378:Chromogranin B; D053381:Secretogranin II; D007334:Insulin-Like Growth Factor I; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D013972:Thyrotropin; D013006:Growth Hormone; D005947:Glucose