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  • In a recent study Neelaveni et al revealed that


    In a recent study, Neelaveni et al. [47] revealed that new thiazolidinedione derivatives (Fig. 6 a and 6 b) produced dual PPARγ and FFAR1 agonistic activity at micromolar concentrations with insulin sensitizing effects and enhanced insulin secretion from the pancreas. These derivatives were reported by these authors to possess the classical topology of the synthetic agonists and the lipophilic tail consists of bulky groups like biphenyl and benzimidazole. Recently, some researchers working in China Pharmaceutical University developed novel FFA1 agonists some of which were found to be efficacious in the management of type 2 diabetes and with low toxicity. For instance, Zheng et al. [48] in their in vivo study using experimental animals, reported that compound, 2- (4-[(2′-chloro-[1,1′-biphenyl]-3-yl) methoxy] phenyl) sulfonyl acetic acid, a phenylsulfonyl acetic Diclofenac mg derivative demonstrated improved glucose tolerance in normal and type 2 diabetic models. The authors further reported that the compound showed a low risk of hypoglycemia in normal fasting rats even at high dose, a common adverse effect that arises from the use of sulfonylureas.
    Potential beneficial role of FFAR1 in non beta-cell Whereas FFAR1 is mainly expressed in the pancreatic beta cells as earlier mentioned, it is also expressed in other tissues at comparatively lower levels such as the alpha cells of the pancreatic islets, where it is involved in regulating glucagon secretion in response to unsaturated FAs [49]. The expression of FFAR1 in the central nervous system is controversial. Whereas Itoh et al. [5] in their studies did not detect expression of GPR40 in the mouse brain; other studies reported FFAR1 expression in human, primate, rat and mouse brains [9,50] respectively. However, the functional role, of FFAR1 in the central nervous system remains unknown, although it has been shown to control pain regulatory systems [50]. Whereas data on experimental or clinical studies supporting the role of intra/extra cellular calcium management in the regulation and functions of FFAR1 is scarce in literature, there are indications that intra/extra cellular calcium management may play a role in the functions of FFAR1. This arises from studies that revealed that FFAR1 is also expressed in osteoclasts (function in breaking down bones to release calcium) and appears to mediate the inhibition of osteoclastogenesis by Fatty acid. Similar to these observations, Cornish et al. [51] observed that FFAR1 mice have reduced bone density. This raises the interesting possibility that FFAR1 agonism, besides improving glucose metabolism, might also protect against osteoporosis. This possibility, however, remains to be formally tested [52]. Finally, FFAR1 has been implicated in the stimulation of breast cancer cell line proliferation in response to oleate [53,54]. This suggests the possibility that chronic administration of GPR40 agonists might have undesirable effect, a possibility that obviously needs to be examined carefully.
    Conflicts of interest
    Introduction Postmenopausal osteoporosis (PMOP) is characterized by a post-menopausal decrease in bone mass and density in women accompanied with a dramatic change in the osteoblast/adipocyte ratio in bone marrow cavity [1], [2]. PMOP promotes bone fragility and susceptibility to bone fractures, which has become a prevalent worldwide concern [3]. Estrogen may be an essential factor in bone mass and density maintenance, and its deficiency leads to the progression of PMOP [4], [5]. Furthermore, physiological estrogen levels help maintain the balance between bone formation, bone resorption and adipocyte maturation by modulating multiple signaling pathways to coordinate distinct cellular functions [6], [7], [8], [9], [10], [11]. However, the underlying mechanisms by which estrogen functions in bone formation are not clearly defined. Several studies have showed greater serum FFA (free fatty acid) concentrations in estrogen-deficient women compared with postmenopausal women receiving estrogen treatment [12], [13], [14], suggesting that estrogen treatment has beneficial effects in postmenopausal women by blocking accelerated FFA delivery into circulation. The underlying mechanism of estrogen-regulated systemic bone metabolism via the modulation of circulating FFA has raised large concerns, as it suggests a relationship between estrogen and FFA in bone formation and bone remodeling [15], [16], [17]. Ward et al. previously showed that FFA combined with low-dose estrogen therapy preserved bone tissue in ovariectomized rats [18]. Moreover, estrogen pretreatment increases FFA release by bradykinin stimulated human osteoblast-like cells [19]. Additionally, Kumar et al. previously reported that E2 stimulates FFA release in a dose-dependent manner with a higher response to E2 in women compared to men [20].