Potential involvement of peroxisome proliferator-activated receptors in the inhibition of mammary lipid synthesis during diet-induced milk fat depression.

The objective of this study was to evaluate the possible role of the peroxisome proliferator-activated receptors (PPAR: PPAR-α, PPAR-β/δ, and PPAR-γ) in diet and CLA-induced milk fat depression (MFD) in dairy cows. We hypothesized that the expression of PPAR, which regulate lipid metabolism and bind to PUFA, could be modulated by biohydrogenation intermediates that induce MFD, thereby interfering with milk fat synthesis. First, tissue profiling revealed that PPAR-α and PPAR-β/δ had low expression in mammary tissue compared with the liver.

Effects of the central melanocortin system on feed intake, metabolic hormones and insulin action in the sheep.

Voluntary feed intake is insufficient to meet the nutrient demands associated with late pregnancy in prolific ewes and early lactation in high-yielding dairy cows. Under these conditions, peripheral signals such as growth hormone and ceramides trigger adaptations aimed at preserving metabolic well-being. Recent work in rodents has shown that the central nervous system-melanocortin (CNS-MC) system, consisting of alpha-melanocyte-stimulating hormone (α-MSH) and agouti-related peptide (AGRP) acting respectively as agonist and antagonist on central MC receptors, contributes to the regulation of some of the same adaptations.

Inflammatory tone in liver and adipose tissue in dairy cows experiencing a healthy transition from late pregnancy to early lactation.

The transition from late pregnancy (LP) to early lactation (EL) in dairy cows is characterized by a major reorganization of the metabolic activities of liver and adipose tissue in support of milk synthesis. This reorganization has been attributed in large part to variation in the plasma concentration and actions of growth hormone, insulin, and other metabolic hormones. A role for the immune system has also been suggested by a near-universal rise in circulating levels of liver-derived acute-phase proteins (APP) in early lactating cows.

Fibroblast growth factor-21 improves insulin action in nonlactating ewes.

During metabolically demanding physiological states, ruminants and other mammals coordinate nutrient use among tissues by varying the set point of insulin action. This set point is regulated in part by metabolic hormones with some antagonizing (e.g.

Effects of birth weight and dietary fat on intake, body composition, and plasma thyroxine in neonatal lambs.

Intrauterine growth restriction (IUGR) is often observed in one of the fetuses carried by well-fed prolific ewes. This condition is the result of an insufficient placental size to cover the nutritional needs of the fetus during the near exponential growth phase of the last trimester. After birth, these IUGR offspring have an elevated appetite and lower maintenance energy requirements, suggesting dysregulation of homeostatic systems governing energy metabolism.

ERAD deficiency promotes mitochondrial dysfunction and transcriptional rewiring in human hepatic cells.

Mitochondrial dysfunction is associated with a variety of human diseases including neurodegeneration, diabetes, nonalcohol fatty liver disease (NAFLD), and cancer, but its underlying causes are incompletely understood. Using the human hepatic cell line HepG2 as a model, we show here that endoplasmic reticulum-associated degradation (ERAD), an ER protein quality control process, is critically required for mitochondrial function in mammalian cells. Pharmacological inhibition or genetic ablation of key proteins involved in ERAD increased cell death under both basal conditions and in response to proinflammatory cytokines, a situation frequently found in NAFLD.

The acute phase protein orosomucoid 1 is upregulated in early lactation but does not trigger appetite-suppressing STAT3 signaling via the leptin receptor.

Dairy cows consume inadequate amounts of feed in early lactation and during conditions and diseases such as excessive fatness, heat stress, and infectious diseases. Affected cows often experience increases in plasma concentrations of acute phase proteins consistent with the negative effect of inflammation on appetite. The acute phase protein orosomucoid 1 (ORM1), also known as alpha-1-acid glycoprotein, was recently reported to reduce appetite in the mouse through its ability to bind the full-length leptin receptor (Ob-Rb) and activate appetite-suppressing signal transducer and activator of transcription 3 (STAT3) signaling.

Dietary Fat Does Not Overcome trans-10, cis-12 Conjugated Linoleic Acid Inhibition of Milk Fat Synthesis in Lactating mice.

Trans-10, cis-12 conjugated linoleic acid (CLA) is a potent inhibitor of milk fat synthesis in the cow and similarly reduces milk fat in rodents. The objective of this study was to determine whether dietary fat can overcome CLA inhibition of milk fat concentration in lactating mice. Wild type C57Bl/6J mice (n = 31) were fed semipurified diets containing either low fat (LF; 4% fat) or high fat (HF; 23.

Fibroblast growth factor-21 (FGF21) administration to early-lactating dairy cows. II. Pharmacokinetics, whole-animal performance, and lipid metabolism.

Dairy cows cope with severe energy insufficiency in early lactation by engaging in intense and sustained mobilization of fatty acids from adipose tissue. An unwanted side effect of this adaptation is excessive lipid accumulation in the liver, which in turn impairs hepatic functions. Mice experiencing increased hepatic fatty acid flux are protected from this condition through coordinated actions of the newly described hormone fibroblast growth factor-21 (FGF21) on liver and adipose tissue.

Fibroblast growth factor-21 (FGF21) administration to early-lactating dairy cows. I. Effects on signaling and indices of insulin action.

Modern dairy cows rely on hormonally driven mechanisms to coordinate the metabolic adaptations needed to meet the energy and nutrient deficits of early lactation. In the case of glucose, dairy cows cope with its scarcity during early lactation via reduced plasma concentrations of insulin and the insulin sensitizing hormone adiponectin and increased insulin resistance. Reduced insulin action promotes diversion of available glucose to the mammary gland but increases susceptibility to diseases if excessive.

Effects of recombinant bovine interleukin-8 (rbIL-8) treatment on health, metabolism, and lactation performance in Holstein cattle III: Administration of rbIL-8 induces insulin resistance in bull calves.

Our previous work has suggested that recombinant bovine interleukin-8 (rbIL-8) treatment might influence cow metabolism. Therefore, this study was conducted to initially assess the effects of systemic administration of rbIL-8 on response to a glucose challenge, blood metabolites, insulin, growth hormone, insulin-like growth factor-1, immune cell populations, and inflammatory parameters in Holstein bull calves. Calves from 30 ± 6 d of life were individually housed and randomly allocated to 1 of 2 treatment groups: rbIL-8 (rbIL-8, n = 10) and control (CTR, n = 8).

Technical note: Effects of pegylation and route of administration on leptin kinetics in newborn lambs1.

Chronic energy insufficiency resulting from inadequate feed intake or increased nutrient demand reduces plasma leptin in ruminants. Treatment of energy-deficient ruminants with exogenous leptin has identified some physiological consequences of reduced plasma leptin, but their full complement remains unknown. Additional leptin-dependent responses could be identified by using strategies that interfere with leptin signaling such as administration of leptin mutants that act as competitive antagonists.

Endoplasmic Reticulum-Associated Degradation (ERAD) Has a Critical Role in Supporting Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells.

The molecular underpinnings of β-cell dysfunction and death leading to diabetes are not fully elucidated. The objective of the current study was to investigate the role of endoplasmic reticulum-associated degradation (ERAD) in pancreatic β-cells. Chemically induced ERAD deficiency in the rat insulinoma cell line INS-1 markedly reduced glucose-stimulated insulin secretion (GSIS).

Intravenous Triacylglycerol Infusion Promotes Ceramide Accumulation and Hepatic Steatosis in Dairy Cows.

Background: Increased plasma free fatty acids (FFAs) impair insulin sensitivity in dairy cows via unknown mechanisms. In nonruminants, saturated FFAs upregulate the hepatic synthesis and secretion of ceramide, which inhibits insulin action.

Objective: We aimed to determine whether an increase in plasma FFAs promotes hepatic and plasma ceramide accumulation in dairy cows.

Time-dependent effect of trans-10,cis-12 conjugated linoleic acid on gene expression of lipogenic enzymes and regulators in mammary tissue of dairy cows.

Trans-10,cis-12 conjugated linoleic acid (CLA) has been identified as an intermediate of rumen fatty acid biohydrogenation that caused milk fat depression (MFD) in the dairy cow. Previous studies in cows experiencing CLA- and diet-induced MFD have identified reduced mammary expression of the master lipogenic regulator sterol response element transcription factor 1 (SREBF1) and many of its dependent genes. To distinguish between primary mechanisms regulating milk fat synthesis and secondary adaptations to the reduction in milk fat, we conducted a time-course experiment.

Variation in x-box binding protein 1 (XBP1) expression and its dependent endoplasmic reticulum chaperones does not regulate adiponectin secretion in dairy cows.

Adiponectin is an insulin-sensitizing hormone produced predominantly by adipose tissue; it circulates as oligomers of 3, 6, 18, or more units. Plasma adiponectin might be involved in the development of insulin resistance in transition dairy cows because it falls to a nadir around parturition. The possibility that this regulation occurs through a post-transcriptional mechanism was suggested in a previous study that showed unchanged adiponectin mRNA abundance combined with reduced expression of endoplasmic reticulum (ER) chaperones implicated in assembly of adiponectin oligomers.

Evaluation of a semi-automated computer algorithm for measuring total fat and visceral fat content in lambs undergoing in vivo whole body computed tomography.

Computed tomography (CT) is a suitable tool for measuring body fat, since it is non-destructive and can be used to differentiate metabolically active visceral fat from total body fat. Whole body analysis of body fat is likely to be more accurate than single CT slice estimates of body fat. The aim of this study was to assess the agreement between semi-automated computer analysis of whole body volumetric CT data and conventional proximate (chemical) analysis of body fat in lambs.

Effect of hormonal and energy-related factors on plasma adiponectin in transition dairy cows.

In transition dairy cows, plasma levels of the insulin-sensitizing hormone adiponectin fall to a nadir at parturition and recover in early lactation. The transition period is also characterized by rapid changes in metabolic and hormonal factors implicated in other species as positive regulators of adiponectin production (i.e.

Effect of circulating glucagon and free fatty acids on hepatic FGF21 production in dairy cows.

Modern dairy cows meet the energy demand of early lactation by calling on hormonally driven mechanisms to increase the use of lipid reserves. In this context, we recently reported that fibroblast growth factor-21 (FGF21), a hormone required for efficient use of lipid reserves in rodents, is upregulated in periparturient dairy cows. Increased plasma FGF21 in early lactation coincides with elevated circulating concentrations of glucagon (GCG) and nonesterified fatty acids (NEFA).

A replicator-specific binding protein essential for site-specific initiation of DNA replication in mammalian cells.

Mammalian chromosome replication starts from distinct sites; however, the principles governing initiation site selection are unclear because proteins essential for DNA replication do not exhibit sequence-specific DNA binding. Here we identify a replication-initiation determinant (RepID) protein that binds a subset of replication-initiation sites. A large fraction of RepID-binding sites share a common G-rich motif and exhibit elevated replication initiation.

Increased plasma leptin attenuates adaptive metabolism in early lactating dairy cows.

Mammals meet the increased nutritional demands of lactation through a combination of increased feed intake and a collection of adaptations known as adaptive metabolism (e.g., glucose sparing via insulin resistance, mobilization of endogenous reserves, and increased metabolic efficiency via reduced thyroid hormones).

XBP1 Regulates the Biosynthetic Capacity of the Mammary Gland During Lactation by Controlling Epithelial Expansion and Endoplasmic Reticulum Formation.

Cells composing the mammary secretory compartment have evolved a high capacity to secrete not only proteins but also triglycerides and carbohydrates. This feature is illustrated by the mouse, which can secrete nearly twice its own weight in milk proteins, triglycerides and lactose over a short 20-day lactation. The coordination of synthesis and export of products in other secretory cells is orchestrated in part by the transcription factor X-box binding protein 1 (XBP1).

Insensitivity of well-conditioned mature sheep to central administration of a leptin receptor antagonist.

Ruminants remain productive during the energy insufficiency of late pregnancy or early lactation by evoking metabolic adaptations sparing available energy and nutrients (e.g. higher metabolic efficiency and induction of insulin resistance).