Analysis of knockout mice suggests a role for VGF in the control of fat storage and energy expenditure.
BACKGROUND
Previous studies of mixed background mice have demonstrated that targeted deletion of Vgf produces a lean, hypermetabolic mouse that is resistant to diet-, lesion-, and genetically-induced obesity. To investigate potential mechanism(s) and site(s) of action of VGF, a neuronal and endocrine secreted protein and neuropeptide precursor, we further analyzed the metabolic phenotypes of two independent VGF knockout lines on C57Bl6 backgrounds.


RESULTS
Unlike hyperactive VGF knockout mice on a mixed C57Bl6-129/SvJ background, homozygous mutant mice on a C57Bl6 background were hypermetabolic with similar locomotor activity levels to Vgf+/Vgf+ mice, during day and night cycles, indicating that mechanism(s) other than hyperactivity were responsible for their increased energy expenditure. In Vgf-/Vgf- knockout mice, morphological analysis of brown and white adipose tissues (BAT and WAT) indicated decreased fat storage in both tissues, and decreased adipocyte perimeter and area in WAT. Changes in gene expression measured by real-time RT-PCR were consistent with increased fatty acid oxidation and uptake in BAT, and increased lipolysis, decreased lipogenesis, and brown adipocyte differentiation in WAT, suggesting that increased sympathetic nervous system activity in Vgf-/Vgf- mice may be associated with or responsible for alterations in energy expenditure and fat storage. In addition, uncoupling protein 1 (UCP1) and UCP2 protein levels, mitochondrial number, and mitochondrial cristae density were upregulated in Vgf-/Vgf- BAT. Using immunohistochemical and histochemical techniques, we detected VGF in nerve fibers innervating BAT and Vgf promoter-driven reporter expression in cervical and thoracic spinal ganglia that project to and innervate the chest wall and tissues including BAT. Moreover, VGF peptide levels were quantified by radioimmunoassay in BAT, and were found to be down-regulated by a high fat diet. Lastly, despite being hypermetabolic, VGF knockout mice were cold intolerant.


CONCLUSIONS
We propose that VGF and/or VGF-derived peptides modulate sympathetic outflow pathways to regulate fat storage and energy expenditure.
Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA. ew2258@columbia.edu
Elizabeth
E
Watson
Samira
S
Fargali
Haruka
H
Okamoto
Masato
M
Sadahiro
Ronald E
RE
Gordon
Tandra
T
Chakraborty
Mark W
MW
Sleeman
Stephen R
SR
Salton
D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000294:innervation / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001823:Body Composition / Q000235:genetics*; D050218:Body Fat Distribution; D001831:Body Temperature / Q000235:genetics; D002151:Calorimetry; D003080:Cold Temperature; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics; D009414:Nerve Growth Factors; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D000071256:Uncoupling Protein 1
D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009414:Nerve Growth Factors; D009479:Neuropeptides; D047495:PPAR gamma; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C512697:Vgf protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase