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  • In contrast to short term effects long term exposure of

    2022-07-29

    In contrast to short-term effects, long-term exposure of beta cells to FFAs impairs insulin secretion and triggers apoptosis [13]. The deleterious effects of FFAs have been linked to altered glucose/fatty 5'-Iodoresiniferatoxin oxidation cycle [13], decreased NADPH content [14], endoplasmic reticulum (ER) stress [15] and partitioning towards formation of toxic ceramide species [16]. Also, FFAR1 signaling has been implicated in the long-term deleterious effects of FFAs [17], [18], [19], [20]. We have recently demonstrated that fatty acid metabolism and FFAR1 signaling act synergistically on insulin secretion [17]. Reduced β-oxidation of fatty acids in the presence of a FFAR1 antagonist pointed out mitochondria as a site where the two pathways may converge [17]. It is known that this organelle is pivotal in beta-cell function. Uncoupling of respiration from ATP synthesis is essential for the regulation of ATP/ADP ratio and insulin secretion [21]; and beta cells depleted of mitochondria are unable to properly change insulin secretion in response to metabolic changes [22], [23]. Taking into account the aforementioned, we decided to investigate the effects of fatty acid metabolism and FFAR1 signaling on mitochondrial function.
    Materials and methods
    Results and discussion
    Conclusions In summary, during palmitate exposure, integrated action of intracellular metabolism of the fatty acid and Gαq-coupled FFAR1 signaling on mitochondrial respiration underlies the synergistic action of the two pathways on insulin secretion.
    Acknowledgments
    The study was funded by the European Commission FP7-project Beta-JUDO (Grant 279153), and Swedish Diabetes Association (Grant DIA 2013-043) and Family Ernfors Foundation (Grant 150430).
    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]. Current studies have identified five orphan G protein-coupled receptors (GPCRs) that can be activated by free fatty acids (FFAs), GPR40, GPR41, GPR43, GPR84, and GPR120. Short-chain fatty acids (FAs) are specific agonists of GPR41 and GPR43 [21] and middle-chain FAs agonize GPR84 [22]. Long-chain FAs can activate GPR40 and GPR120 [23], [24]. However, the role of these FFAs in osteogenesis has not been clearly defined. Until now, GPR40 has been shown to be expressed in osteoclasts and osteocytes [25]. Furthermore, Wittrant et al. and Mabilleau et al. found that GPR40 can protect from bone loss via the inhibition of osteoclast differentiation [26] and can induce osteocyte apoptosis [25]. However, a direct role for GPR40 in osteoblasts has not been defined.