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 mitigating the negative energy balance prompted by copious milk synthesis and limited dry matter intake. Past research has demonstrated that lipolysis in the adipose organ is a complex process that includes not only the activation of lipolytic pathways in response to neural, hormonal, or paracrine stimuli, but also important changes in the structure and cellular distribution of the tissue in a process known as adipose tissue remodeling. This process involves an inflammatory response with immune cell migration, proliferation of the cellular components of the stromal vascular fraction, and changes in the extracellular matrix. This review summarizes current knowledge on lipolysis in dairy cattle, expands on the new field of adipose tissue remodeling, and discusses how these biological processes affect transition cow health and productivity.

Despite major advances in our understanding of transition and early lactation cow physiology and the use of advanced dietary, medical, and management tools, at least half of early lactation cows are reported to develop disease and over half of cow deaths occur during the first week of lactation. Excessive lipolysis, usually measured as plasma concentrations of free fatty acids (FFA), is a major risk factor for the development of displaced abomasum, ketosis, fatty liver, and metritis, and may also lead to poor lactation performance. Lipolysis triggers adipose tissue (AT) remodeling that is characterized by enhanced humoral and cell-mediated inflammatory responses and changes in its distribution of cellular populations and extracellular matrix composition. Uncontrolled AT inflammation could perpetuate lipolysis, as we have observed in cows with displaced abomasum, especially in those animals with genetic predisposition for excessive lipolysis responses. Efficient transition cow management ensures a moderate rate of lipolysis that is rapidly reduced as lactation progresses. Limiting FFA release from AT benefits immune function as several FFA are known to promote dysregulation of inflammation. Adequate formulation of pre- and postpartum diet reduces the intensity of AT lipolysis. Additionally, supplementation with niacin, monensin, and rumen-protected methyl donors (choline and methionine) during the transition period is reported to minimize FFA release into systemic circulation. Targeted supplementation of energy sources during early lactation improves energy balance and increases insulin concentration, which limits AT lipolytic responses. This review elaborates on the mechanisms by which uncontrolled lipolysis triggers inflammatory disorders. Details on current nutritional and pharmacological interventions that aid the modulation of FFA release from AT and their effect on immune function are provided. Understanding the inherent characteristics of AT biology in transition and early lactation cows will reduce disease incidence and improve lactation performance.

During the periparturient period, lipolysis in adipose tissue (AT) mobilizes fatty acid reserves to meet high energy needs of dairy cows. This physiological response is accompanied by the synthesis and secretion of a plethora of proteins (adipokines) and lipid products that modulate metabolic functions. In the AT, lipolysis generates free radicals (FR), including reactive oxygen species, and leads to a remodeling process characterized by an inflammatory response. In the AT of healthy cows with adequate lipolytic responses, antioxidant defenses neutralize FR, and the inflammation associated with remodeling is rapidly resolved. The control of these processes is orchestrated by numerous inflammatory and oxidative stress (OS)-related pathways identified by recent transcriptomic and proteomic analyses. For example, parturition and the onset of lactation enhance the transcription and translation of complement and acute-phase proteins and, at the same time, enrich antioxidant defenses that neutralize FR, including Nrf2. However, in cows with exacerbated and protracted lipolysis, the production of FR rapidly depletes antioxidant systems, and OS develops. The harmful effects of OS in AT include activating inflammatory responses and inhibiting insulin signaling within AT. By intensifying AT inflammation, OS impairs adipocyte response to insulin. This leads to a vicious circle where OS exacerbates AT lipolysis and inflammation, which further promotes OS. This review summarizes current knowledge on the mechanisms that modulate AT inflammatory responses and OS during the periparturient period of dairy cows.

High concentrations of plasma nonesterified fatty acids (NEFA), a direct measure of lipolysis, are considered a risk factor for displaced abomasum (DA) and other clinical diseases. In nonruminants, uncontrolled lipolysis is commonly associated with adipose tissue macrophage (ATM) infiltration. In dairy cows, recent studies report ATM infiltration in specific adipose depots during the first week of lactation. Depending on their phenotype, ATM can be broadly classified as classically activated (M1) or alternatively activated (M2). The M1 ATM are considered pro-inflammatory, whereas M2 ATM enhance inflammation resolution. Currently, it is not known whether multiparous transition cows with DA have increased ATM infiltration, and the predominant phenotype of these mononuclear cells remains unclear. The objective of this study was to characterize ATM infiltration into different adipose tissue depots in transition cows with DA (days in milk=7.8±4.6 d; body condition score=2.95±0.10; n=6). Serum samples and biopsies from omental (OM) and subcutaneous (SC) fat depots were obtained during corrective surgery for DA. In an effort to compare ATM infiltration in DA cows with that of healthy cows in anabolic state (AS), adipose biopsies and blood samples were collected from nonlactating, nongestating dairy cows at the time of slaughter (body condition score=3.75±0.12; n=6). Adipose tissues were digested and cells from the stromal vascular fraction (SVF) were analyzed using flow cytometry to establish cell surface expression of specific macrophage markers including CD14, CD11c, CD163, and CD172a. Tissue sections were analyzed by immunohistochemistry to assess ATM localization. Cows with DA were ketotic and had plasma NEFA above 1.0 mEq/L. The same group of cows had significant infiltration of ATM in OM characterized by increased numbers of SVF cells expressing CD14 and CD172a. At the same time, expression of CD11c, and CD163 was significantly higher in SVF from OM and SC of DA cows compared with those from AS animals. Expression of M1 macrophage inflammatory phenotype-related genes CCL2, IL6, and TNFα in SVF from cows with DA was significantly higher than that in healthy cows (AS). Significant populations of ATM in OM and SC depots of cows with DA were localized in multiple cellular aggregates that included multinucleated cells. In contrast, ATM in AS cows were fewer and randomly localized in both SC and OM. Together, these results indicate that infiltration of classically activated ATM is a concurrent finding in DA cases and may be associated with metabolic stress around parturition contributing to the pro-inflammatory status of transition dairy cows. Future studies are needed to establish whether ATM infiltration is more pronounced in cows with DA compared with healthy dairy cows at the same lactation stage and if this increased mononuclear immune cell trafficking has any pathophysiological significance.

Intense and protracted adipose tissue (AT) fat mobilization increases the risk of metabolic and inflammatory periparturient diseases in dairy cows. This vulnerability increases when cows have endotoxemia-common during periparturient diseases such as mastitis, metritis, and pneumonia-but the mechanisms are unknown. Fat mobilization intensity is determined by the balance between lipolysis and lipogenesis. Around parturition, the rate of lipolysis surpasses that of lipogenesis, leading to enhanced free fatty acid release into the circulation. We hypothesized that exposure to endotoxin (ET) increases AT lipolysis by activation of classic and inflammatory lipolytic pathways and reduction of insulin sensitivity. In experiment 1, subcutaneous AT (SCAT) explants were collected from periparturient (n = 12) Holstein cows at 11 ± 3.6 d (mean ± SE) before calving, and 6 ± 1 d and 13 ± 1.4 d after parturition. Explants were treated with the endotoxin lipopolysaccharide (LPS; 20 µg/mL; basal = 0 µg/mL) for 3 h. The effect of LPS on lipolysis was assessed in the presence of the β-adrenergic agonist and promoter of lipolysis isoproterenol (ISO; 1 µM; LPS+ISO). In experiment 2, SCAT explants were harvested from 24 nonlactating, nongestating multiparous Holstein dairy cows and exposed to the same treatments as in experiment 1 for 3 and 7 h. The effect of LPS on the antilipolytic responses induced by insulin (INS = 1 µL/L, LPS+INS) was established during ISO stimulation [ISO+INS, LPS+ISO+INS]. The characterization of lipolysis included the quantification of glycerol release and the assessment of markers of lipase activity [adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and phosphorylated HSL Ser563 (pHSL)], and insulin pathway activation (AKT, pAKT) using capillary electrophoresis. Inflammatory gene networks were evaluated by real-time quantitative PCR. In periparturient cows, LPS increased AT lipolysis by 67 ± 12% at 3 h across all time points compared with basal. In nonlactating cows, LPS was an effective lipolytic agent at 3 h and 7 h, increasing glycerol release by 115 ± 18% and 68.7 ± 16%, respectively, relative to basal. In experiment 2, LPS enhanced ATGL activity with minimal HSL activation at 3 h. In contrast, at 7 h, LPS increased HSL phosphorylation (i.e., HSL activity) by 123 ± 11%. The LPS-induced HSL lipolytic activity at 7 h coincided with the activation of the MEK/ERK inflammatory pathway. In experiment 2, INS reduced the lipolytic effect of ISO (ISO+INS: -63 ± 18%) and LPS (LPS+INS: -45.2 ± 18%) at 3 h. However, the antilipolytic effect of INS was lost in the presence of LPS at 7 h (LPS+INS: -16.3 ± 16%) and LPS+ISO+INS at 3 and 7 h (-3.84 ± 23.6% and -21.2 ± 14.6%). Accordingly, LPS reduced pAKT:AKT (0.11 ± 0.07) compared with basal (0.18 ± 0.05) at 7 h. Our results indicated that exposure to LPS activated the classic and inflammatory lipolytic pathways and reduced insulin sensitivity in SCAT. These data provide evidence that during endotoxemia, dairy cows may be more susceptible to lipolysis dysregulation and loss of adipocyte sensitivity to the antilipolytic action of insulin.

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.