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United States Department of Agriculture

Agricultural Research Service

Title: Characterization of Tusc5, a Unique Adipocyte Gene Co-Expressed in Peripheral Somatosensory Neurons)

item Oort, Pieter
item Warden, Craig
item Baumann, Thomas
item Knotts, Trina
item Adams, Sean

Submitted to: Molecular and Cellular Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/22/2007
Publication Date: 7/1/2007
Citation: Oort, P.J., Warden, C.H., Baumann, T.K., Knotts, T.A., Adams, S.H. 2007. Characterization of Tusc5, a Unique Adipocyte Gene Co-Expressed in Peripheral Somatosensory Neurons. Molecular and Cellular Endocrinology. 276:24-35, 2007.

Interpretive Summary: Obese people have increased susceptibility to diabetes, cardiovascular disease, and other disorders including neuropathy. How these conditions are driven by excess white adipose tissue (WAT) is not completely understood. Despite great strides to identify hormonal and transcriptional factors controlling fat cell development and function, these processes have not been fully defined. Advances in this area promise to yield a better understanding of the relationship between body fat and disease, and will uncover biomarkers of disease progression and predictors of susceptibility. We have identified Tusc5 as a unique temperature-regulated adipose gene with triggered expression during 3T3-L1 adipocyte differentiation. Genetics studies using crosses of four mouse strains point to Tusc5 as a possible obesity gene candidate. Remarkably, in addition to robust expression in mature adipocytes, Tusc5 is highly-expressed in somatosensory nerve ganglia (involved in sensation of pain, ambient temperature, etc.), suggesting an important role in both traditional fat depots and in peripheral nervous system (PNS) cells.

Technical Abstract: Tumor suppressor candidate 5 (Tusc5, GenBank nomenclature) is a cold-repressed gene encoding a member of the CD225 domain-containing family, identified through analysis of transcripts differentially-expressed in brown adipose tissue (BAT) with changes in ambient temperature. Tusc5 mRNA was found to be robustly-expressed in mouse white adipose tissue (WAT) and BAT relative to other tissues, with relatively high expression in human WAT (adipocytes) and hibernoma. Unexpectedly, Tusc5 was found to be co-expressed in primary somatosensory neurons. Tusc5 mRNA was markedly increased from trace levels in pre-adipocytes to significant levels in developing 3T3-L1 adipocytes, coincident with several mature adipocyte markers (phosphoenolpyruvate carboxykinase 1, GLUT4, adipsin, leptin). Like several genes with relevance to adipocyte function and metabolism, Tusc5 mRNA abundance was regulated by the peroxisome proliferator activated receptor-y (PPARy) agonist GW1929 (1 µg/mL) in 3T3-L1 cells: i.e., significantly increased by 18 hr treatment to levels >10-fold (pre-adipocytes) to ~1.5-fold (mature adipocytes) of controls (p<0.0001, treatment effect). Considering its high adipose expression and chromosomal position near an adiposity QTL originally identified in HG.CAST-(D11Mit260-D11Mit255)N(6)(HG11) x C57BL/6J-hg/hg (HG) crosses {Farber & Medrano 2006 #1020}, an evaluation of Tusc5 as an obesity candidate gene identified a significant QTL for gonadal fat weight at the Tusc5 locus, which also corresponded to LOD peaks for retroperitoneal fat (p<0.1), and femoral fat pad and total fat weights (p>0.1). A complimentary study in humans compared Tusc5 coding sequence variation in lean (average BMI 19.5, n=377) and obese (average BMI 39.0; n=381) subjects. While several missense mutations were identified, their allele frequencies were similar between the two groups and no deletions or premature stop codons were detected. Thus, sequence changes in the Tusc5 coding sequence are not likely to be major contributors to the obese phenotype observed in this human population. The unusual co-expression of Tusc5 in fat cells and sensory neurons suggests that Tusc5 activities are shared between adipocytes and peripheral sensory neurons. Such a relationship would signal a previously-underappreciated fat-somatosensory interaction linking adiposity with environmental cues, with implications for understanding the molecular etiology of obesity- and type 2 diabetes-related neuropathies.

Last Modified: 05/29/2017
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