It is interesting to note that

It is interesting to note that the long and short forms of GPR120 exist at different basal levels of phosphorylation, with the short form demonstrating a greater degree of constitutive activity [12]. Importantly, Burns and Moniri [12] showed that, upon activation, the long and short isoforms of GPR120 are phosphorylated to the same extent by α-LA and DHA. It is further suggested by Watson et al.[13] that the long isoform of GPR120 exhibits preferential coupling to β-arrestin signaling. Other studies also indicate that there could be a partial loss of function associated with the long isoform of GPR120 6, 14. Thus, it remains important to determine physiological relevance of the two isoforms and, subsequently, whether pharmaceutical agents act preferentially through the short or long isoform and their associated signaling cascades. To date, downstream effectors of GPR120 activation have been identified as the mitogen-activated kinases, extracellular regulated kinase 1/2 (ERK1/2) 6, 8, 32, c-Jun N-terminal kinase (JNK), inhibitor of kappa B kinase β (IKKβ), inhibitor of kappa B (IκB), transforming growth factor β activated kinase 1 (TAK1) [8], caspase-3 [32] and members of the insulin signaling cascade including Akt (also known as protein kinase B), insulin receptor beta (IRβ), insulin receptor substrate (IRS) 1 and 2, and the lipogenic protein stearoyl-CoA desaturase 1 [5]; all of which support a role for GPR120 in mediating inflammation and metabolic homeostasis.
Physiological functions of GPR120 and the implications for metabolic disease GPR120 is proposed as a drug candidate largely for the treatment of metabolic diseases and, in view of the current literature, agonists at this receptor are expected to be of benefit 5, 6, 7, 8, 33. Metabolic diseases are often the consequence of a chronic Z-IETD-FMK imbalance where intake exceeds requirements leading to a prolonged positive energy balance [34]. This is complicated by hedonic and hedonistic factors influencing energy intake and expenditure and, over the longer term, is reflected by an increase in body adiposity 34, 35, paralleled by increased risk of co-morbid conditions such as T2DM and CVD. Here, we examine the effect of GPR120 on parameters that are known to influence metabolic health and how these might be targeted in the treatment of disease states that manifest perturbed metabolic function at the tissue-specific and systemic levels. Again, the development of chemical activators and/or inhibitors selective to GPR120 will be invaluable in determining the extent to which GPR120 is responsible for these effects. This might be especially relevant in separating the effects of GPR40 given the similar patterns of expression and dual specificity of LCFAs and chemical compounds developed to date.
Adipogenesis GPR120 is abundantly expressed in adipocyte and adipose tissue extracts 5, 7, 8, yet is undetectable in pre-adipocytes 7, 21. Moreover, GPR120 expression increases in parallel with lipid accumulation in the cells upon induction of differentiation in 3T3-L1 cells 7, 21. Small interference RNA against GPR120 was shown to reduce the expression of adipogenic genes and reduced lipid droplet accumulation in 3T3-L1 adipocytes [7]. Taken together, these data support the contention that GPR120 is an adipogenic receptor. Importantly, adipocyte hypertrophy is a key pathogenic feature in the development of obesity. Interestingly, in the study by Gotoh et al.[7], GPR120 mRNA expression was increased by high fat feeding in subcutaneous, epididymal and mesenteric adipose tissues. Ichimura et al.[5] also demonstrated that the expression of GPR120 mRNA is increased in human subcutaneous and omental adipose tissues from obese compared with lean individuals. Both of these studies suggest that GPR120 activity could be augmented by a high dietary lipid load. Given the adipogenic potential of GPR120, it might be expected that augmented activity at GPR120 could promote increased adiposity. Thus, GPR120 activation might be expected to promote obesity. However, GPR120−/− mice exhibited significantly greater adipocyte area (hypertrophy) than wild-type mice, an effect that persisted in mice fed a normal or high fat diet [5]. Consistent with adipocyte hypertrophy, GPR120−/− mice fed a high fat diet gained significantly more fat mass than their wild-type counterparts [5]. Bodyweight was not observed to be different between GPR120−/− and wild-type mice on a normal chow diet 5, 8, suggesting GPR120 has an important role in regulating bodyweight in the presence of a positive energy balance and is indeed protective against diet-induced obesity.