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Adipokine expression dynamics and roles in modulating adipose tissue (AT) lipolysis in transition dairy cows
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Elevated concentrations of plasma fatty acids in transition dairy cows are significantly associated with increased disease susceptibility and poor lactation performance. The main source of plasma fatty acids throughout the transition period is lipolysis from adipose tissue depots. During this time, plasma fatty acids serve as a source of calories m...
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Context 1
... proteins are termed adi- pokines and are produced by the cellular components of AT, such as adipocytes and cells of the stromal vascular fraction (SVF), including immune, vascular, and adipo- cyte progenitor cells. Despite the ever-expanding list of adipokines, which now accounts for over 300 secretory products [48], few have been studied in dairy cattle (Table 2). Among these signaling molecules, adiponectin and leptin are almost exclusively secreted by AT; while others, such as resistin and retinol binding protein 4, are also produced in the liver. ...
Citations
... Dairy cows' genetics tend to prioritize milk production at the detriment of future reproductive investment (i.e., resumption of cycling, longer calving interval) (Stearns, 1992). Lactation promotes lipolysis over lipogenesis, causing high-yielding cows to mobilize lipid reserves regardless of their energy balance status to meet the demands (Contreras et al., 2017;Vernon et al., 1995). Through a gene-based mapping and pathway analysis, Ha et al. (2015) implicated several biological pathways (steroid hormone biosynthesis, drug metabolism, glycerophospholipid metabolism, starch and sucrose metabolism, ether lipid metabolism) F I G U R E 6 Bar charts of the enriched term for the biological pathways (a) and biological processes (b) driving the genetic correlation between the urea and fertility traits. ...
Unfavorable genetic correlations between milk production, fertility, and urea traits have been reported. However, knowledge of the genomic regions associated with these unfavorable correlations is limited. Here, we used the correlation scan method to identify and investigate the regions driving or antagonizing the genetic correlations between production vs. fertility, urea vs. fertility, and urea vs. production traits. Driving regions produce an estimate of correlation that is in the same direction as the global correlation. Antagonizing regions produce an estimate in the opposite direction of the global estimates. Our dataset comprised 6567, 4700, and 12,658 Holstein cattle with records of production traits (milk yield, fat yield, and protein yield), fertility (calving interval) and urea traits (milk urea nitrogen and blood urea nitrogen predicted using milk‐mid‐infrared spectroscopy), respectively. Several regions across the genome drive the correlations between production, fertility, and urea traits. Antagonizing regions were confined to certain parts of the genome and the genes within these regions were mostly involved in preventing metabolic dysregulation, liver reprogramming, metabolism remodeling, and lipid homeostasis. The driving regions were enriched for QTL related to puberty, milk, and health‐related traits. Antagonizing regions were mostly related to muscle development, metabolic body weight, and milk traits. In conclusion, we have identified genomic regions of potential importance for dairy cattle breeding. Future studies could investigate the antagonizing regions as potential genomic regions to break the unfavorable correlations and improve milk production as well as fertility and urea traits.
... As ATGL and HSL account for >90% of the triacylglycerol hydrolysis (26), they are considered pivotal indicators of lipolysis (27)(28)(29). Furthermore, perilipin-1, which encircles lipid droplets within adipocytes, has been revealed to play a role in lipolysis (30,31). Perilipin-1 was shown to inhibit lipolysis while concurrently promoting lipid synthesis and lipid droplet formation (32). ...
Chrysosplenium flagelliferum (CF) is known for its anti-inflammatory, antioxidant and antibacterial activities. However, there is a lack of research on its other pharmacological properties. In the present study, the bifunctional roles of CF in 3T3-L1 and RAW264.7 cells were investigated, focusing on its anti-obesity and immunostimulatory effects. In 3T3-L1 cells, CF effectively mitigated the accumulation of lipid droplets and triacylglycerol. Additionally, CF downregulated the peroxisome proliferator-activated receptor (PPAR)-γ and CCAAT/enhancer-binding protein α protein levels; however, this effect was impeded by the knockdown of β-catenin using β-catenin-specific small interfering RNA. Consequently, CF-mediated inhibition of lipid accumulation was also decreased. CF increased the protein levels of adipose triglyceride lipase and phosphorylated hormone-sensitive lipase, while decreasing those of perilipin-1. Moreover, CF elevated the protein levels of phosphorylated AMP-activated protein kinase and PPARγ coactivator 1-α. In RAW264.7 cells, CF enhanced the production of pro-inflammatory mediators, such as nitric oxide (NO), inducible NO synthase, interleukin (IL)-1β, IL-6 and tumor necrosis factor-α, and increased their phagocytic capacities. Inhibition of Toll-like receptor (TLR)-4 significantly reduced the effects of CF on the production of pro-inflammatory mediators and phagocytosis, indicating its crucial role in facilitating these effects. CF-induced increase in the production of pro-inflammatory mediators was controlled by the activation of c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-κB pathways, and TLR4 inhibition attenuated the phosphorylation of these kinases. The results of the pesent study suggested that CF inhibits lipid accumulation by suppressing adipogenesis and inducing lipolysis and thermogenesis in 3T3-L1 cells, while stimulating macrophage activation via the activation of JNK and NF-κB signaling pathways mediated by TLR4 in RAW264.7 cells. Therefore, CF simultaneously exerts both anti-obesity and immunostimulatory effects.
... The AT is also an endocrine organ that regulates biological functions, including immune function, angiogenesis, glucose homeostasis, food intake, blood pressure, and reproduction [2]. In dairy cattle, as in other mammals, AT regulates systemic metabolism. ...
... Similarly, in late lactation cows, feed restriction-induced lipolysis results in enhanced immune cell infiltration within the AT [11]. This adaptive response enhances the production of lipogenic and antioxidant substances that maintain AT homeostasis [2]. However, when adipose tissue becomes insensitive to lipogenic or antioxidative signals, excessive lipolysis and dysregulated inflammation ensue [12]. ...
During the periparturient period, dairy cows exhibit negative energy balance due to limited appetite and increased energy requirements for lactogenesis. The delicate equilibrium between energy availability and expenditure puts cows in a state of metabolic stress characterized by excessive lipolysis in white adipose tissues (AT), increased production of reactive oxygen species, and immune cell dysfunction. Metabolic stress, especially in AT, increases the risk for metabolic and inflammatory diseases. Around parturition, cows are also susceptible to endotoxemia. Bacterial-derived toxins cause endotoxemia by promoting inflammatory processes and immune cell infiltration in different organs and systems while impacting metabolic function by altering lipolysis, mitochondrial activity, and insulin sensitivity. In dairy cows, endotoxins enter the bloodstream after overcoming the defense mechanisms of the epithelial barriers, particularly during common periparturient conditions such as mastitis, metritis, and pneumonia, or after abrupt changes in the gut microbiome. In the bovine AT, endotoxins induce a pro-inflammatory response and stimulate lipolysis in AT, leading to the release of free fatty acids into the bloodstream. When excessive and protracted, endotoxin-induced lipolysis can impair adipocyte’s insulin signaling pathways and lipid synthesis. Endotoxin exposure can also induce oxidative stress in AT through the production of reactive oxygen species by inflammatory cells and other cellular components. This review provides insights into endotoxins’ impact on AT function, highlighting the gaps in our knowledge of the mechanisms underlying AT dysfunction, its connection with periparturient cows’ disease risk, and the need to develop effective interventions to prevent and treat endotoxemia-related inflammatory conditions in dairy cattle.
... Tissue macrophages have been shown to produce leptin in human medicine [103], which in turn, leads to an increase in the concentrations of inflammatory markers (haptoglobin and cortisol) [104]. In dairy cows during early lactation, there is adipose-specific IR and high rates of lipid mobilization [12], and the infiltration of adipose tissue macrophages (ATM) is a response to this intense lipolysis [105,106]. Therefore, the role of macrophages represents a contributing factor to the promotion of inflammatory responses in IR in these transition cows. In the context of human IR, macrophages are recruited to insulin-sensitive tissues such as the liver and AT via chemokines (Figure 3) [107]. ...
Simple Summary
This review critically examined the literature on the interaction between insulin resistance (IR) and metabolic inflammation in transition dairy cows. Our review emphasizes how IR and metabolic inflammation mutually influence each other, leading to heightened lipolysis, immune activation, and tissue inflammatory pathways. These processes contribute to a harmful cycle where inflammatory mediators exacerbate IR and metabolic inflammation. While transient IR and metabolic inflammation are natural adaptations in transitioning cows, this review highlights the increased disease risk in over-conditioned cows. Understanding these interactions is crucial for managing metabolic disorders in dairy herds and promoting animal health, welfare, and productivity.
Abstract
During the transition period, dairy cows exhibit heightened energy requirements to sustain fetal growth and lactogenesis. The mammary gland and the growing fetus increase their demand for glucose, leading to the mobilization of lipids to support the function of tissues that can use fatty acids as energy substrates. These physiological adaptations lead to negative energy balance, metabolic inflammation, and transient insulin resistance (IR), processes that are part of the normal homeorhetic adaptations related to parturition and subsequent lactation. Insulin resistance is characterized by a reduced biological response of insulin-sensitive tissues to normal physiological concentrations of insulin. Metabolic inflammation is characterized by a chronic, low-level inflammatory state that is strongly associated with metabolic disorders. The relationship between IR and metabolic inflammation in transitioning cows is intricate and mutually influential. On one hand, IR may play a role in the initiation of metabolic inflammation by promoting lipolysis in adipose tissue and increasing the release of free fatty acids. Metabolic inflammation, conversely, triggers inflammatory signaling pathways by pro-inflammatory cytokines, thereby leading to impaired insulin signaling. The interaction of these factors results in a harmful cycle in which IR and metabolic inflammation mutually reinforce each other. This article offers a comprehensive review of recent advancements in the research on IR, metabolic inflammation, and their intricate interrelationship. The text delves into multiple facets of physiological regulation, pathogenesis, and their consequent impacts.
... Given the interrelatedness of hyperketonemia with other metabolic disorders, as well as the potential for hyperketonemia to occur secondary to other disorders that result in reduced feed intake (Oetzel, 2004;McArt et al., 2012b), the ability to quantify multiple metabolites simultaneously provides a unique opportunity for comprehensive diagnostics. For example, quantifying NEFA aids in identifying cows that are actively mobilizing adipose tissue stores (Grummer, 2008;Contreras et al., 2017) which may increase ketogenesis. ...
The periparturient period for dairy cows is a metabolically dynamic time period where the cow is adjusting from gestation to the onset of lactation. Metabolic disorders such as ketosis, hypocalcemia, and fatty liver occur during this time; however, tools to diagnose these diseases on-farm is limited. The need for compact metabolite quantification devices that can quantify metabolites on farm from whole blood samples is warranted. The purpose of this study was to validate a portable blood analyzer (PBA) by analyzing metabolites on privately owned dairy farms in southcentral Wisconsin. Additional tests were completed to determine if plasma metabolite quantification was similar to whole-blood quantification. Two phases were conducted on two separate farms to complete these analyses and data were analyzed by Bland-Altman plot and correlations. Metabolites quantified from whole blood samples included albumin, alanine and aspartate aminotransferases, β-hydroxybutyrate, blood urea nitrogen, total calcium, cholesterol, creatinine kinase, γ-glutamyl transferase, glucose, magnesium, nonesterified fatty acids, phosphorous, and total protein and were analyzed in the lab after plasma separation to determine gold-standard laboratory concentrations. Across Phase 1 and 2, whole-blood PBA metabolite concentrations resulted in similar results compared to the laboratory assays. For plasma analyzed on the PBA, overall results were positively correlated, but robustness was dependent upon initial validation results indicating some metabolites are suitable for plasma quantification on the device. These results indicate that the PBA is a viable on-farm metabolite quantification tool that will be valuable for on-farm diagnosis of metabolic stress and dysfunction in transition dairy cows.
... In addition to playing a role in lipid storage and release, the metabolism of adipose tissue actively regulates homeostasis and the inflammatory response, making it crucial for studying sphingolipid biology (90). Intense adipose tissue remodeling accompanied by increased expression of an inflammatory phenotype by adipose tissue macrophages may impair the metabolic function of adipose tissue in dairy cows due to physiological changes associated with parturition, the onset of lactation, or prolonged periods of lipolysis (or both) (91). ...
Dairy cows must undergo profound metabolic and endocrine adaptations during their transition period to meet the nutrient requirements of the developing fetus, parturition, and the onset of lactation. Insulin resistance in extrahepatic tissues is a critical component of homeorhetic adaptations in periparturient dairy cows. However, due to increased energy demands at calving that are not followed by a concomitant increase in dry matter intake, body stores are mobilized, and the risk of metabolic disorders dramatically increases. Sphingolipid ceramides involved in multiple vital biological processes, such as proliferation, differentiation, apoptosis, and inflammation. Three typical pathways generate ceramide, and many factors contribute to its production as part of the cell’s stress response. Based on lipidomic profiling, there has generally been an association between increased ceramide content and various disease outcomes in rodents. Emerging evidence shows that ceramides might play crucial roles in the adaptive metabolic alterations accompanying the initiation of lactation in dairy cows. A series of studies also revealed a negative association between circulating ceramides and systemic insulin sensitivity in dairy cows experiencing severe negative energy balance. Whether ceramide acts as a driver or passenger in the metabolic stress of periparturient dairy cows is an unknown but exciting topic. In the present review, we discuss the potential roles of ceramides in various metabolic dysfunctions and the impacts of their perturbations. We also discuss how this novel class of bioactive sphingolipids has drawn interest in extrahepatic tissue insulin resistance and immunometabolic disorders in transition dairy cows. We also discuss the possible use of ceramide as a new biomarker for predicting metabolic diseases in cows and highlight the remaining problems.
... Mastitis occurs frequently in the periparturient period of high-yielding cows [1]. During this period, excessive fat mobilization is mobilized to maintain successful lactation and combat negative energy balance, which may lead to overproduction of reactive oxygen species (ROS) [2,3]. Studies have confirmed that excessive ROS production could lead to oxidative stress, changing the immunity and anti-inflammatory function of perinatal cows, increasing their susceptibility to mastitis [4,5]. ...
Selenium (Se) deficiency disrupts intracellular REDOX homeostasis and severely deteriorates immune and anti-inflammatory function in high-yielding periparturient dairy cattle. To investigate the damage of extracellular vesicles derived from Se-deficient MAC-T cells (SeD-EV) on normal mammary epithelial cells, an in vitro model of Se deficiency was established. Se-deficient MAC-T cells produced many ROS, promoting apoptosis and the release of inflammatory factors. Extracellular vesicles were successfully isolated by ultrahigh-speed centrifugation and identified by transmission electron microscopy, particle size analysis, and surface markers (CD63, CD81, HSP70, and TSG101). RNA sequencing was performed on exosomal RNA. A total of 9393 lncRNAs and 63,155 mRNAs transcripts were identified in the SeC and SeD groups, respectively, of which 126 lncRNAs and 955 mRNAs were differentially expressed. Furthermore, SeD-EV promoted apoptosis of normal MAC-T cells by TUNEL analysis. SeD-EV significantly inhibited Bcl-2, while Bax and Cleaved Caspase3 were greatly increased. Antioxidant capacity (CAT, T-AOC, SOD, and GSH-Px) was inhibited in SeD-EV-treated MAC-T cells. Additionally, p-PERK, p-eIF2α, ATF4, CHOP, and XBP1 were all elevated in MAC-T cells supplemented with SeD-EV. In addition, p-PI3K, p-Akt, and p-mTOR were decreased strikingly by SeD-EV. In conclusion, SeD-EV caused oxidative stress, thus triggering apoptosis and inflammation through endoplasmic reticulum stress and the PI3K-Akt-mTOR signaling pathway, which contributed to explaining the mechanism of Se deficiency causing mastitis.
... Another study introduced IL-6 as a hub gene in the fat lipolysis of thin-tailed sheep breeds [29]. This gene is well known to be a lipolytic factor that stimulates fat lipolysis and fatty acid oxidation in humans [72,73], dairy cows [74], rats [75], mice [76,77], and sheep [29]. Thus, the up-regulation of the aforementioned genes in thin-tailed sheep might be closely related to lipolysis. ...
Simple Summary
For this paper, we investigated the differences in adipose tissue deposition between sheep breeds with fat and thin tails, relying on advanced techniques like meta-analyses and machine learning to analyze gene expression data. Our findings revealed key genes associated with fat metabolism, shedding light on the genetic factors influencing tail fat in sheep. Notably, three specific genes (POSTN, K35, and SETD4) were identified as significant biosignatures related to fat deposition. This innovative approach (combining data analysis and machine learning) enhances our understanding of how to optimize fat deposition in sheep breeds, which holds potential for more efficient animal breeding strategies and carcass fat reduction.
Abstract
It has been shown that tail fat content varies significantly among sheep breeds and plays a significant role in meat quality. Recently, significant efforts have been made to understand the physiological, biochemical, and genomic regulation of fat deposition in sheep tails in order to unravel the mechanisms underlying energy storage and adipose tissue lipid metabolism. RNA-seq has enabled us to provide a high-resolution snapshot of differential gene expression between fat- and thin-tailed sheep breeds. Therefore, three RNA-seq datasets were meta-analyzed for the current work to elucidate the transcriptome profile differences between them. Specifically, we identified hub genes, performed gene ontology (GO) analysis, carried out enrichment analyses of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and validated hub genes using machine learning algorithms. This approach revealed a total of 136 meta-genes, 39 of which were not significant in any of the individual studies, indicating the higher statistical power of the meta-analysis. Furthermore, the results derived from the use of machine learning revealed POSTN, K35, SETD4, USP29, ANKRD37, RTN2, PRG4, and LRRC4C as substantial genes that were assigned a higher weight (0.7) than other meta-genes. Among the decision tree models, the Random Forest ones surpassed the others in adipose tissue predictive power fat deposition in fat- and thin-tailed breeds (accuracy > 0.85%). In this regard, combining meta-analyses and machine learning approaches allowed for the identification of three important genes (POSTN, K35, SETD4) related to lipid metabolism, and our findings could help animal breeding strategies optimize fat-tailed breeds’ tail sizes.
... Therefore, energy from body fat reserves can be nearly twice as much as that derived from muscles. During periods of limited energy availability, the body's fat reserves are the first to be mobilized through the process of adipose tissue lipolysis, releasing TG [77]. Several factors influence body fat reserves, including (1) reproductive potential [78]; (2) negative energy balance [79]; (3) feeding level; and (4) nutrient composition [80]. ...
This study utilized fifty bull calves of the Continental × British crossbreed, with an average body weight of 147.0 ± 1.67 kg (BW), in a completely randomized design. The objective was to examine the impact of varying levels and duration of calcium propionate (CaPr) supplementation on the growth performance, body fat reserves, serum metabolites, and hemogram of high-risk newly received stocker calves. These calves were individually housed and fed a received diet for 56 d. The calves received the following treatments: (1) no CaPr (CTL), (2) 20 g CaPr/calf/d, (3) 40 g CaPr/calf/d, (4) 60 g CaPr/calf/d, and (5) 80 g CaPr/calf/d at 14, 28, 42, and 56 d after their arrival. Supplementing with 20 g CaPr from 28 to 56 d after arrival increased average daily gain (ADG) and BW (p < 0.05), and DMI was not affected (p > 0.05). This was reflected at 28 d with increases (p < 0.05) in the ADG/DMI ratio and longissimus muscle area (LMA), and at 56 d in back fat thickness (BFT) and fat thickness at the rump (FTR). Also, with 20 g, blood urea nitrogen decreased (p < 0.05), and increases were observed in the activity of gamma glutamyltransferase, monocytes (quadratic trend, p < 0.07), and granulocytes % (quadratic effect, p < 0.03). However, as the level of CaPr increased during the first 14 d after arrival, daily water intake, creatinine, total cholesterol, mean corpuscular hemoglobin concentration (linear effect, p < 0.05), globulin, calcium, and mean corpuscular volume (linear trend, p = 0.08) increased, while alkaline phosphatase (linear trend, p = 0.07) and lymphocytes (linear effect, p = 0.05) decreased. Finally, the different levels of CaPr supplementation did not produce any significant effects or differences (p > 0.05) in the remaining serum metabolites and hemogram (p > 0.05). Ultimately, the inclusion of 20 g CaPr/calf/d in the diet for 28 d in newly received stocker calves increased ADG, ADG/DMI ratio, and LMA. If extended to 42 or 56 d, the increases in ADG persisted, but there was also a rise in body fat reserves (BFT and FTR) at the expense of a reduction in the ADG/DMI ratio. Furthermore, the different supplementation levels did not impact the reference range for most serum metabolites or the health of stocker calves.
... Therefore, energy from body fat reserves can be nearly twice as much as that derived from muscles. When energy is limited in the organism, body fat reserves are the first to be depleted through adipose tissue lipolysis, releasing TG [65]. Consequently, body fat reserves are influenced by factors such as 1) reproductive potential [66]; 2) negative energy balance [67]; 3) feeding level; and 4) nutrient composition [68]. ...
Fifty bull calves of the Continental × British crossbred (147.0 ± 1.67 kg body weight, BW) were used in a completely randomized design to investigate the effect varying levels and duration of calcium propionate (CaPr) supplementation on the growth performance, body fat reserves, serum metabolites, and hemogram of high-risk newly received stocker calves. These calves were individually housed and fed a received-diet for 56 d. The calves received the following treatments: 1) No CaPr (CTL), 2) 20 g CaPr/calf/d, 3) 40 g CaPr/calf/d, 4) 60 g CaPr/calf/d, and 5) 80 g CaPr/calf/d, during 14, 28, 42 and 56 d the after arrival. The supplementation with 20 g CaPr from 28 to 56 d after arrival increases average daily gain (ADG) and BW (p < 0.05), and DMI is not affected (p > 0.05). This is reflected at 28 d with increases (p < 0.05) in ADG:DMI ratio and longissimus muscle area (LMA), and at 56 d in back fat thickness (BFT) y fat thickness at the rump (FTR). Also, with 20 g, blood urea nitrogen decreased (p < 0.05); and increases were observed in the activity of gamma glutamyltransferase, monocytes (quadratic trend, p < 0.07) and granulocytes% (quadratic effect, p < 0.03). However, as the level of CaPr increased during the first 14 d after arrival, daily water intake, creatinine, total cholesterol, mean corpuscular hemoglobin concentration (linear effect, p < 0.05), globulin, calcium and mean corpuscular volume (linear trend, p = 0.08) increased, while alkaline phosphatase (linear trend, p = 0.07) and lymphocytes (linear effect, p = 0.05) decreased. Finally, the different levels of CaPr supplementation did not produce any significant effects or differences (p > 0.05), in the remaining serum metabolites and hemogram (p > 0.05). Ultimately, the inclusion of 20 g CaPr/calf/d in the diet for 28 d in newly received stocker calves increases ADG, ADG:DMI ratio and LMA. If extended to 42 or 56 d, the increases in ADG persist, but there is also a rise in body fat reserves (BFT and FTR) at the expense of a reduction in ADG:DMI ratio. Furthermore, the different supplementation levels did not impact the reference range for most serum metabolites or the health of stocker calves.
