A disputed evidence on obesity: comparison of the effects of Rcan2(-/-) and Rps6kb1(-/-) mutations on growth and body weight in C57BL/6J mice.
It is widely accepted that body weight and adipose mass are tightly regulated by homeostatic mechanisms, in which leptin plays a critical role through hypothalamic pathways, and obesity is a result of homeostatic disorder. However, in C57BL/6J mice, we found that Rcan2 increases food intake and plays an important role in the development of age- and diet-induced obesity through a leptin-independent mechanism. RCAN2 was initially identified as a thyroid hormone (T3)-responsive gene in human fibroblasts. Expression of RCAN2 is regulated by T3 through the PI3K-Akt/PKB-mTOR-Rps6kb1 signaling pathway. Intriguingly, both Rcan2(-/-) and Rps6kb1(-/-) mutations were reported to result in lean phenotypes in mice. In this study we compared the effects of these two mutations on growth and body weight in C57BL/6J mice. We observed reduced body weight and lower fat mass in both Rcan2(-/-) and Rps6kb1(-/-) mice compared to the wild-type mice, and we reported other differences unique to either the Rcan2(-/-) or Rps6kb1(-/-) mice. Firstly, loss of Rcan2 does not directly alter body length; however, Rcan2(-/-) mice exhibit reduced food intake. In contrast, Rps6kb1(-/-) mice exhibit abnormal embryonic development, which leads to smaller body size and reduced food intake in adulthood. Secondly, when fed a normal chow diet, Rcan2(-/-) mice weigh significantly more than Rps6kb1(-/-) mice, but both Rcan2(-/-) and Rps6kb1(-/-) mice develop similar amounts of epididymal fat. On a high-fat diet, Rcan2(-/-) mice gain body weight and fat mass at slower rates than Rps6kb1(-/-) mice. Finally, using the double-knockout mice (Rcan2(-/-) Rps6kb1(-/-)), we demonstrate that concurrent loss of Rcan2 and Rps6kb1 has an additive effect on body weight reduction in C57BL/6J mice. Our data suggest that Rcan2 and Rps6kb1 mutations both affect growth and body weight of mice, though likely through different mechanisms.
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
Jing
J
Zhao
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
Shi-Wei
SW
Li
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
Qian-Qian
QQ
Gong
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
Ling-Cui
LC
Ding
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
Ye-Cheng
YC
Jin
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
Jian
J
Zhang
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
Jian-Gang
JG
Gao
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
Xiao-Yang
XY
Sun
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001724:Birth Weight; D001823:Body Composition; D049628:Body Size; D001835:Body Weight; D004822:Epididymis / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics*; D014284:Triiodothyronine
C486303:Dscr1l1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D014284:Triiodothyronine; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1
Body weight regulation; Growth; Obesity; Rcan2 gene; Rps6kb1 gene