Submitted to: Journal of Nutrition
Publication Type: Peer reviewed journal
Publication Acceptance Date: 1/1/2008
Publication Date: 2/9/2008
Publication URL: jn.nutrition.org/cgi/reprint/138/5/841
Citation: Oort, P.J., Knotts, T.A., Grino, M., Naour, N., Bastard, J., Clement, K., Ninkina, N., Buchman, V.L., Permana, P., Luo, X., Pan, G., Dunn, T.N., Adams, S.H. 2008. y-Synuclein is an Adipocyte-Neuron Gene Coordinately-Expressed with Leptin & Increased in Obesity. Journal of Nutrition. 138:841-848, 2008. Interpretive Summary: Identifying the subcellular and systemic networks which connect energy balance, tissue fuel utilization patterns, and body composition will be an important step toward understanding how metabolic homeostasis and healthy body weight are regulated and maintained. The remarkable molecular and physiological shifts which take place in response to changes in ambient temperature in rodents has been leveraged to identify several genes and pathways which participate in these networks, through transcriptome analysis of temperature-dependent gene expression changes in thermogenic mouse brown adipose tissue (BAT) (2-4). Those studies uncovered a cold-repressed white adipose tissue (WAT) and BAT gene originally termed Adipose Abundant Protein (5), now termed tumor suppressor candidate 5 (Tusc5, nomenclature derived from a report indicating loss of the gene in certain lung cancer tissues (6)). Recently, rat Tusc5 has been identified as a BAT and WAT gene down-regulated by cold exposure, reduced in obese epididymal WAT, and induced during brown adipocyte maturation (7;8). Based on the presence of a CD225 cell growth-regulating protein domain, up-regulation of expression by a PPAR' agonist, and induction of the gene following exit from the mitotic clonal expansion phase of 3T3-L1 adipogenesis, we proposed a working model in which white adipocyte Tusc5 activities are associated with entry into or persistence of the fully mature, growth-arrested metabolic and structural phenotype (1). Identification of Tusc5 and other adipocyte proteins that modulate cell growth is important to understand mechanisms that underlie adipose malleability (“plasticity”) characterized by phenotypic change, cell type conversion (fat cell transdifferentiation), and/or adipocyte proliferation (see (9) for review).
Technical Abstract: Objective: Recently, we characterized tumor suppressor candidate 5 (Tusc5) as an adipocyte-neuron peroxisome proliferator activated receptor-y (PPARy) target gene (1). Our objective herein was to identify additional candidate genes that play shared roles in neuron-fat physiology. Research Methods and Procedures: Synuclein-y (SNCG), a marker of peripheral neurons and implicated in cell proliferation/cancer was found to be strongly expressed in white adipose tissue (WAT) and peripheral nervous system ganglia using the SymAtlas expression database, verified by quantitative PCR of murine and human tissue panels. Expression of SNCG was determined during adipogenesis, and analyzed in subcutaneous (SC) and/or visceral adipose tissue (VAT) in obese and non-obese humans. Results: SNCG mRNA was increased from trace levels in pre-adipocytes to significant levels in mature 3T3-L1 adipocytes, and was responsive to the PPARy agonist GW1929: increased by ~1.5-fold in pre-adipocytes (p<0.001 vs. untreated controls) but decreased in differentiated adipocytes (i.e., by 66% day 7 post-differentiation). SNCG mRNA was increased ~1.7-fold in obese Pima Indian SC adipocytes (p = 0.003), up to 2-fold in SC and VAT of obese French cohorts, and SNCG adipose expression correlated with leptin transcript levels in human SC and VAT (Pearson’s r = 0.887, p<0.0001, n = 44). Discussion: Since SNCG has pro-proliferative activities in non-adipocytes and is associated with cancer progression, we suspected that SNCG expression would be increased in situations in which WAT plasticity/expansion are engaged. Consistent with this postulate, WAT SNCG transcript was consistently increased in human obesity, supporting the idea that SNCG represents a newly-identified candidate protein involved with adipocyte growth phenotypes.