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.
View Article and Find Full Text PDFAm J Physiol Regul Integr Comp Physiol
March 2022
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.
View Article and Find Full Text PDFIntrauterine 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.
View Article and Find Full Text PDFMitochondrial 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.
View Article and Find Full Text PDFTrans-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.
View Article and Find Full Text PDFChronic 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.
View Article and Find Full Text PDFThe 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).
View Article and Find Full Text PDFBackground: 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.
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.
View Article and Find Full Text PDFAm J Physiol Regul Integr Comp Physiol
November 2017
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).
View Article and Find Full Text PDFMammalian 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.
View Article and Find Full Text PDFMammals 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).
View Article and Find Full Text PDFCells 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).
View Article and Find Full Text PDFBackground: Trans-10, cis-12 conjugated linoleic acid (10,12 CLA) is a potent inhibitor of milk fat synthesis in mammals. In the cow, 10 g/d of 10,12 CLA specifically and reversibly inhibits mammary lipogenesis, whereas substantially higher doses are not specific and cause a generalized inhibition of milk synthesis.
Objective: The objective of this study was to validate a lactating mouse model by establishing the dose response, specificity, and reversibility of the inhibition of milk fat synthesis by 10,12 CLA.
Am J Physiol Regul Integr Comp Physiol
August 2014
Female mammals call on hormonally driven metabolic adaptations to meet the energy demand of late pregnancy and lactation. These maternal adaptations preserve limiting nutrients and promote their transfer to the uterus during pregnancy or mammary gland during lactation. The novel metabolic hormone fibroblast growth factor-21 (FGF21) was recently shown to increase suddenly at the onset of lactation in dairy cows, but whether FGF21 is induced during the reproductive cycle of other mammals is unknown.
View Article and Find Full Text PDFAbstract Milk fat synthesis of ruminants can be inhibited by intermediates of ruminal fatty acid biohydrogenation including trans-10, cis-12 conjugated linoleic acid (CLA). These biohydrogenation intermediates signal a coordinated downregulation of genes involved in mammary FA synthesis, transport, and esterification. We have previously reported decreased mammary expression of sterol response element-binding protein 1 (SREBP1), SREBP1-activating proteins, and thyroid hormone-responsive spot 14 (S14) in the cow during diet-induced milk fat depression (MFD), and treatment with trans-10, cis-12 CLA.
View Article and Find Full Text PDFThe very long chain n-3 (ω-3) polyunsaturated fatty acids (VLCn3PUFAs) are potent regulators of hepatic lipid synthesis, but their effect on lipid synthesis in the lactating mammary gland is less well investigated. The objective of the present study was to examine effects of fish oil (FO) supplementation on mammary lipogenesis and the expression of lipogenic genes in mammary and hepatic tissues of lactating mice. Beginning on day 6 of lactation and continuing for 7 d, female C57BL/6J mice (n = 8/diet) were fed 1 of 3 dietary treatments: a 5%-fat diet containing mainly saturated fatty acids (FAs) (low-fat control) or 2 10%-fat diets, 1 enriched with FO as a source of VLCn3PUFAs and the other enriched with a safflower/palm oil mixture (high-fat control) as a source of oleic acid.
View Article and Find Full Text PDFIn rodents and primates, insulin resistance develops during pregnancy and fades after parturition. In contrast, dairy cows and other ruminants maintain insulin resistance in early lactation (EL). This adaptation favors mammary glucose uptake, an insulin-independent process, at a time when the glucose supply is scarce.
View Article and Find Full Text PDFSuperactive ovine leptin antagonist (SOLA) was prepared by rational mutagenesis of the ovine leptin antagonist L39A/D40A/F41A mutant prepared previously in our lab by mutating wild type leptin to D23L/L39A/D40A/F41A. SOLA was expressed in Escherichia coli as insoluble inclusion bodies, refolded and purified to homogeneity (as evidenced by SDS-PAGE and analytical gel filtration) by ion-exchange chromatography. The purified protein was mono-pegylated at its N terminus by 20-kDa linear pegylation reagent.
View Article and Find Full Text PDFIn many mammals, lactation success depends on substantial use of lipid reserves and requires integrated metabolic activities between white adipose tissue (WAT) and liver. Mechanisms responsible for this integration in lactation are poorly understood, but data collected in other conditions of elevated lipid use suggest a role for fibroblast growth factor-21 (FGF21). To address this possibility in the context of lactation, we studied high-yielding dairy cows during the transition from late pregnancy (LP) to early lactation (EL).
View Article and Find Full Text PDFPHIP was isolated as an insulin receptor substrate 1 (IRS-1) interacting protein. To date, the physiological roles of PHIP remain unknown. Here we show that mice lacking PHIP1, the full-length isoform of PHIP, are born at normal size but suffer a 40% growth deficit by weaning.
View Article and Find Full Text PDFMice lacking leptin (ob/ob) or its full-length receptor (db/db) are obese and reproductively incompetent. Fertility, pregnancy, and lactation are restored, respectively, in ob/ob mice treated with leptin through mating, d 6.5 post coitum, and pregnancy.
View Article and Find Full Text PDFThe hypothesis that increases in the concentration of the anorectic peptide leptin may be responsible for the immune-mediated reduction in feed intake (FI) during gastrointestinal parasitism in sheep was investigated. In a 2 x 2 x 2 factorial design, the first factor was age at the start of infection (5 months old v. 17 months old).
View Article and Find Full Text PDFNormal postnatal growth is dependent in part on overlapping actions of GH and IGF-I. These actions reflect GH stimulation of IGF-I production in liver and extrahepatic tissues, representing respectively the endocrine and autocrine/paracrine arms of the IGF system. Recent experiments in genetically modified mice show that each source of IGF-I can compensate for absence of the other but do not resolve their relative role in postnatal growth.
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