Adipose tissue (AT) is a major modulator of metabolic functions by regulating energy storage and acting as an endocrine organ. In periparturient dairy cows, increased AT mobilization of free fatty acids (FFA) is one a major adaptive mechanism to cope with higher energy demand for rapid fetal growth and the onset of lactation. As lactation progresses, lipolysis rates decrease, and lipogenesis replenishes triacylglycerol (TAG) stores in adipocytes. However, dysregulated metabolic responses, characterized by altered AT sensitivity to hormonal and endocrine changes around parturition, lead to a massive release of FFA into circulation and an increased susceptibility of cows to disease. These maladaptive responses are underlined by an altered secretory pattern of adipokines and a marked unbalance in lipolysis and lipogenesis rates, favoring TAG breakdown in adipocytes. Thus, identifying adipokines that modulate AT function in periparturient dairy cows can facilitate the development of novel management, nutritional, or pharmaceutical interventions to reduce disease incidence. Fetuin-A (FetA; alpha-2-Heremans-Schmid glycoprotein, AHSG) is an adipokine that functions as a carrier of FFA in plasma and is associated with insulin-mediated inhibition of lipolysis and stimulation of lipogenesis in humans. FetA increases the incorporation of fatty acids (FA) into intracellular lipids and enhances cellular TAG in human cells. However, the mechanisms by which FetA induces TAG synthesis are not defined. FetA has also anti-inflammatory properties by inhibiting the production of pro-inflammatory cytokines and acting as a negative acute-phase protein (APP) in acute inflammation. These findings suggest that FetA may also be involved in lipid mobilization and inflammation in AT of dairy cows. In our first in vivo study with periparturient dairy cows, we observed that serum and AT FetA expression decreased at the onset of lactation when lipogenesis was downregulated and plasma FFA was increased. FetA expression dynamics in AT were analogous to the patterns of lipogenic markers suggesting its link with lipid mobilization in AT of dairy cows. We also demonstrated that FetA is negative-APP locally in AT of dairy cows. These results suggest that FetA could support physiological adaptations to NEB in AT of periparturient dairy cows. To explore the potential roles of FetA on AT lipid mobilization of dairy cows, we developed an in vitro model for culturing bovine adipocytes that closely mimics the in vivo AT environment. For the first time, we reported an abundant expression and secretion of FetA by primary bovine adipocytes, thus suggesting a potential autocrine effect of FetA in AT of dairy cows. We observed that FetA attenuates lipolytic responses and enhances both, FA uptake and TAG accumulation in bovine adipocytes. Our results reveal that the upregulation of the expression and activity of 1-acylglycerol-3-phosphate acyltransferase (AGAPT2), a rate limiting lipogenic enzyme for TAG synthesis, may be a potential mechanism by which FetA enhances lipogenic function of bovine adipocytes. Overall, our results indicate that FetA is a lipogenic adipokine with anti-inflammatory function in the AT of dairy cows. Our findings provide evidence that FetA could buffer increased plasma FFA during negative energy balance by stimulating AGAPT2 activity and the use of excess FFA for TAG synthesis in AT of dairy cows. The genetic selection of cows by variations of the FetA coding gene associated with its anti-lipolytic and pro-lipogenic functions (already known in humans), the identification of dietary supplements (i.e. FA) that enhance FetA function, as well as the parenteral use of FetA to stimulate AGAPT2 activity, could serve as potential strategies to be tested and implemented in dairy cows.
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