Endocrine Abstracts

The rising prevalence of type 2 diabetes can be directly related to increasing levels of population obesity and associated insulin resistance. Adipose tissue has neuroanatomically well characterized sympathetic innervation (with activation initiating lipid mobilization), but little evidence to support the presence of a (putatively counter-regulatory) parasympathetic input (Bartness & Song 2007). Parasympathetic actions are mediated through muscarinic acetylcholine receptors (mAChR). Knockout of the M3 mAChR subtype in mouse models is associated with loss of visceral fat, and a significant (approximately 22%) reduction in weight compared to the wild-type (Yamada et al. 2001); a central orexigenic mechanism has been predicted.

We hypothesize that adipocytes and their precursors functionally express one or more mAChR subtypes, affecting direct, end organ, parasympathetic modulation of adipose tissue metabolism. To examine this, murine (3T3-L1, derived from white adipose tissue) and human (PAZ-6, derived from brown adipose tissue) cell lines, and human primary cultures, have been utilised as experimental models.

Both cell lines express M1, M3 and M4 mAChR during differentiation; there was no evidence of either M2 or M5 mAChR expression. M4 RNA transcripts are present in the greatest concentrations (up to 7.43/1000ARP, compared with 0.54/1000ARP (M1) and 0.24/1000ARP (M3) in 3T3-L1 cells). M3 expression increased in both 3T3-L1 and PAZ-6 cell lines during adipogenesis, whilst M1 and M4 exhibited little variation over the time (see below; mean fold difference in expression (n=3) compared to a basal value of 1).

The presence of mAChR RNA transcripts supports the hypothesis; translation is under investigation. The observed responsiveness in M3 expression is compatible with a key regulatory role in adipogenesis, and offers another therapeutic target in the management of obesity.