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  • Kibble, Milla; Khan, Suleiman A.; Ammad-ud-din, Muhammad; Bollepalli, Sailalitha; Palviainen, Teemu; Kaprio, Jaakko; Pietiläinen, Kirsi H.; Ollikainen, Miina (2020)
    We combined clinical, cytokine, genomic, methylation and dietary data from 43 young adult monozygotic twin pairs (aged 22-36 years, 53% female), where 25 of the twin pairs were substantially weight discordant (delta body mass index > 3 kg m(-2)). These measurements were originally taken as part of the TwinFat study, a substudy of The Finnish Twin Cohort study. These five large multivariate datasets (comprising 42, 71, 1587, 1605 and 63 variables, respectively) were jointly analysed using an integrative machine learning method called group factor analysis (GFA) to offer new hypotheses into the multi-molecular-level interactions associated with the development of obesity. New potential links between cytokines and weight gain are identified, as well as associations between dietary, inflammatory and epigenetic factors. This encouraging case study aims to enthuse the research community to boldly attempt new machine learning approaches which have the potential to yield novel and unintuitive hypotheses. The source code of the GFA method is publically available as the R package GFA.
  • Qin, Nanbing; Bayat, Ali-Reza; Trevisi, Erminio; Minuti, Andrea; Kairenius, Piia; Viitala, Sirja; Mutikainen, Mervi; Leskinen, Heidi; Elo, Kari Tapani; Kokkonen, Tuomo Juhani; Vilkki, Johanna (2018)
    To investigate the metabolic (.11, ! in the adipose tissue (AT) of dairy cows under milk fat depression (MFD), 30 cows were randomly allocated to a control diet, a conjugated linoleic acid (CLA)-supplemented diet, or a high-starch diet supplemented with a mixture of sunflower and fish oil (2:1; as HSO diet) from 1 to 112 d in milk. Performance of animals, milk yield, milk composition, energy balance, and blood metabolites were measured during lactation. Quantitative PCR analyses were conducted on the AT samples collected at wk 3 and 15 of lactation. The CLA and HSO diets considerably depressed milk fat yield and milk fat content at both wk 3 and 15 in the absence of significant changes in milk protein and lactose contents. In addition, the HSO diet lowered milk yield at wk 15 and decreased dry matter intake of cows from wk 3 to 15. Compared with the control, both CLA and HSO groups showed reduced body weight loss, improved energy balance, and decreased plasma concentrations of nonesterified fatty acids and beta-hydroxybutyrate at early lactation. The gene expression analyses reflected suppressed lipolysis in AT of the CLA and HSO groups compared with the control at wk 3, as suggested by the downregulation of hormone-sensitive lipase and fatty acid binding protein 4 and the upregulation of perilipin 2. In addition, the HSO diet promoted lipogenesis in AT at wk 15 through the upregulation of 1-acylglycerol-3-phosphate O-acyltransferase 2, mitochondria' glycerol-3-phosphate acyltransferase, perilipin 2, and peroxisome proliferator-activated receptor gamma. The CLA diet likely regulated insulin sensitivity in AT as it upregulated the transcription of various genes involved in insulin signaling, inflammatory responses, and ceramide metabolism, including protein kinase B2, nuclear factor kappa B1, toll-like receptor 4, caveolin 1, serine palmitoyltransferase long chain base subunit 1, and N-acylsphingosine amidohydrolase 1. In contrast, the HSO diet resulted in little or no change in the pathways relevant to insulin sensitivity. In conclusion, the CLA and HSO diets induced a shift in energy partitioning toward AT instead of mammary gland during lactation through the regulation of different pathways.
  • Salin, S.; Vanhatalo, A.; Jaakkola, S.; Elo, K.; Taponen, J.; Boston, R. C.; Kokkonen, T. (2018)
    High energy intake in the dry period has reportedly had adverse effects on mobilization of body reserves, dry matter intake, and productivity of dairy cows. We investigated whether grass silage (GS) fed ad libitum (high energy intake, HEI; 141% of daily metabolizable energy requirements) in an 8-wk dry period affects metabolic adaptation-specifically, peripheral insulin resistance-compared with a total mixed ration consisting of GS, wheat straw, and rapeseed meal (55/40/5%; controlled energy intake, CEI; 108% of metabolizable energy/d) fed ad libitum. Multiparous Ayrshire dairy cows (n = 16) were used in a randomized complete block design until 8 wk after parturition. Commercial concentrates were fed 1 and 2 kg/d during the last 10 to 6 and 5 to 0 d before the expected calving date, respectively. Postpartum, a similar lactation diet with ad libitum access to GS and increasing concentrate allowance (maximum of 16 kg/d) was offered to all. The HEI group gained more body weight and had higher plasma insulin, glucose, and beta-hydroxybutyrate concentrations than the CEI group prepartum. Postpartal plasma glucose tended to be higher and milk yield was greater from wk 5 onward for HEI compared with CEI cows. An intravenous glucose tolerance test (IVGTT) was performed at -13 +/- 5 d and 9 +/- 1 d relative to calving. The HEI cows had greater insulin response to glucose load and smaller area under the response curve for glucose than CEI cows in prepartal IVGTT. Thus, compensatory insulin secretion adapted to changes in insulin sensitivity of the peripheral tissues, preserving glucose tolerance of HEI cows. Higher insulin levels were needed in HEI cows than in CEI cows to elicit a similar decrement of nonesterified fatty acid concentration in prepartal wurr, suggesting reduced inhibition of lipolysis by insulin in HEI cows before parturition. In conclusion, high energy intake of moderately digestible GS with low concentrate feeding in the close-up dry period did not have adverse effects on metabolic adaptation, insulin sensitivity, and body mobilization after parturition. Instead, this feeding regimen was more beneficial to early-lactation performance than GS-based total mixed ration diluted with wheat straw.
  • Qin, Nanbing; Kokkonen, Tuomo Juhani; Salin, Siru; Seppänen-Laakso, Tuulikki; Taponen, Juhani Olavi; Vanhatalo, Aila Orvokki; Elo, Kari Tapani (2018)
    The liver of dairy cow naturally undergoes metabolic adaptation during the periparturient period in response to the increasing demand for nutrients. The hepatic adaptation is affected by prepartal energy intake level and is potentially associated with inflammatory responses. lb study the changes in the liver function during the periparturient period, 16 cows (body condition score = 3.7 +/- 0.3, mean +/- standard deviation; parity = second through fourth) were allocated to a grass silage-based controlled-energy diet (104 MJ/d) or a high-energy diet (135 MJ/d) during the last 6 wk before the predicted parturition. Liver samples were collected by biopsy at 8 d before the predicted parturition (-8 d) and at 1 and 9 d after the actual parturition (1 and 9 d). The lipidomic profile of liver samples collected at -8 and 9 d was analyzed using ultra performance liquid chromatography-mass spectrometry-based lipidomics. Liver samples from all the time points were subjected to microarray analysis and the subsequent pathway analysis with Ingenuity Pathway Analysis software (Ingenuity Systems, Mountain View, CA). Prepartal energy intake level affected hepatic gene expression and lipidomic profiles prepartum, whereas little or no effect was observed postpartum. At. 8 d, hepatic lipogenesis was promoted by prepartal high-energy feeding through the activation of X receptor/retinoid X receptor pathway and through increased transcription of thyroid hormone-responsive (THRSP). Hepatic inflammatory and acute phase responses at -8 d were suppressed (z-score = -2.236) by prepartal high-energy feeding through the increase in the mRNA abundance of suppressor of cytokine signaling 3 (SOCS9) and the decrease in the mRNA abundance of interleukin 1 (IL1), nuclear factor kappa B 1 (NFKB1), apolipoprotein A1 (APOA1), serum amyloid A3 (SAA3), haptoglobin (HP), lipopolysaccharide-binding protein (LBP), and inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3). Moreover, prepartal high-energy feeding elevated hepatic concentrations of C18- (7%), C20- (17%), C21(26%), C23-sphingomyelins (26%), and total saturated sphingomyelin (21%). In addition, cows in both groups displayed increased lipogenesis at the gene expression level after parturition and alterations in the concentration of various sphingolipids between the first and last samplings. In conclusion, prepartal high-energy feeding promoted lipogenesis and suppressed inflammatory and acute phase responses in the liver before parturition, whereas only minor effects were observed after parturition.
  • Herbers, Elena; Patrikoski, Mimmi; Jokinen, Riikka; Wagner, Anita; Hassinen, Antti; Heinonen, Sini; Miettinen, Susanna; Peltoniemi, Hilkka; Pirinen, Eija; Pietiläinen, Kirsi H. (2022)
    Mitochondrial dysfunction in white adipose tissue is strongly associated with obesity and its metabolic complications, which are important health challenges worldwide. Human adipose-derived stromal/stem cells (hASCs) are a promising tool to investigate the underlying mechanisms of such mitochondrial dysfunction and to subsequently provide knowledge for the development of treatments for obesity-related pathologies. A substantial obstacle in using hASCs is that the key compounds for adipogenic differentiation in vitro increase mitochondrial uncoupling, biogenesis, and activity, which are the signature features of brown adipocytes, thus altering the white adipocyte phenotype towards brown-like cells. Additionally, commonly used protocols for hASC adipogenic differentiation exhibit high variation in their composition of media, and a systematic comparison of their effect on mitochondria is missing. Here, we compared the five widely used adipogenic differentiation protocols for their effect on metabolic and mitochondrial phenotypes to identify a protocol that enables in vitro differentiation of white adipocytes and can more faithfully recapitulate the white adipocyte phenotype observed in human adipose tissue. We developed a workflow that included functional assays and morphological analysis of mitochondria and lipid droplets. We observed that triiodothyronine- or indomethacin-containing media and commercially available adipogenic media induced browning during in vitro differentiation of white adipocytes. However, the differentiation protocol containing 1 mu M of the peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist rosiglitazone prevented the browning effect and would be proposed for adipogenic differentiation protocol for hASCs to induce a white adipocyte phenotype. Preserving the white adipocyte phenotype in vitro is a crucial step for the study of obesity and associated metabolic diseases, adipose tissue pathologies, such as lipodystrophies, possible therapeutic compounds, and basic adipose tissue physiology.