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7 Pág., Identifying metabolite signatures associated with obesity and related diseases might represent a valuable preventive and therapeutic tool to predict subjects at risk, establish an accurate prognosis, and monitor treatment success. The current cross-sectional study is aimed to evaluate the metabolite profile of diet-induced obesity in a porcine model of leptin resistance. Six Iberian female pigs prone to develop obesity (OB) were ad libitum fed a fat-enriched diet (HFD) for 82 days. Five lean Iberian sows (CON) in a maintenance diet served as controls. At the end of the dietary treatments, all animals were sacrificed, and plasma, liver, and muscle samples were immediately collected for nuclear magnetic resonance analysis. In plasma, signals corresponding to betaine, glycerophosphocholine/phosphocholine, glycine, and glutamate were decreased; and the valine signal was increased in OB sows compared to controls. Similarly, the betaine signal was decreased in the liver. No differences were detected in muscle. The observed metabolite changes suggest alterations in branched chain amino-acid metabolism and the methionine-homocysteine cycle, which have been previously associated with obesity-related diseases and type 2 diabetes in human observational studies. The current study supports the utilization of the leptin resistant Iberian pig for further interventional research in the field., This research received no external funding.

We recently demonstrated that in utero heat stress (IUHS) alters future tissue accretion in pigs, but whether this is a conserved response among species, is due to the direct effects of heat stress (HS) or mediated by reduced maternal feed intake (FI) is not clear. Study objectives were to compare the quantity and rate of tissue accretion in rats exposed to differing in utero thermal environments while eliminating the confounding effect of dissimilar maternal FI. On d3 of gestation, pregnant Sprague-Dawley rats (189.0±5.9g BW) were exposed to thermoneutral (TN; 22.2±0.1°C; n=8), or HS conditions (cyclical 30 to 34°C; n=8) until d18 of gestation. A third group was pair-fed to HS dams in TN conditions (PFTN; 22.2±0.1°C; n=8) from d4 to d19 of gestation. HS increased dam rectal temperature (p=0.01; 1.3°C) compared to TN and PFTN mothers, and reduced FI (p=0.01; 33%) compared to TN ad libitum fed controls. Although litter size was similar (p=0.97; 10.9 pups/litter), pup birth weight was reduced (p=0.03; 15.4%) in HS compared to PFTN and TN dams. Two male pups per dam [n=8 in utero TN (IUTN); n=8 IUHS; n=8 in utero PFTN (IUPFTN)] were selected from four dams per treatment based on similar gestation length, and body composition was determined using dual-energy x-ray absorptiometry (DXA) on d26, d46, and d66 of postnatal life. Whole-body fat content increased (p=0.01; 11.2%), and whole-body lean tissue decreased (p=0.01; 2.6%) in IUPFTN versus IUTN and IUHS offspring. Whole-body composition was similar between IUHS and IUTN offspring. Epididymal fat pad weight increased (p=0.03; 21.6%) in IUPFTN versus IUHS offspring. In summary and in contrast to pigs, IUHS did not impact rodent body composition during this stage of growth; however, IUPFTN altered the future hierarchy of tissue accretion.

In utero hyperthermia can cause a variety of developmental issues, but how it alters mammalian body temperature during adolescence is not well-understood. Study objectives were to determine the extent to which in utero hyperthermia affects future phenotypic responses to a heat load. Pregnant first parity pigs were exposed to thermal neutral (TN) or heat stress (HS) conditions during the entire gestation. Of the resultant offspring, 12 were housed in TN conditions, and 12 were maintained in HS conditions for 15 days. Adolescent pigs in HS conditions had increased rectal temperature and respiration rate (RR) compared to TN pigs, regardless of gestational treatment. Within the HS environment, no gestational difference in RR was detected; however, GHS pigs had increased rectal temperature compared to GTN pigs. As rectal temperature increased, GTN pigs had a more rapid increase in RR compared to the GHS pigs. Adolescent HS decreased nutrient intake, and body weight gain, but neither variable was statistically influenced by gestational treatments. In summary, in utero HS compromises the future thermoregulatory response to a thermal insult.

Proper insulin homeostasis appears critical for adapting to and surviving a heat load. Further, heat stress (HS) induces phenotypic changes in livestock that suggest an increase in insulin action. The current study objective was to evaluate the effects of HS on whole-body insulin sensitivity. Female pigs (57 ± 4 kg body weight) were subjected to two experimental periods. During period 1, all pigs remained in thermoneutral conditions (TN; 21°C) and were fed ad libitum. During period 2, pigs were exposed to: (i) constant HS conditions (32°C) and fed ad libitum (n = 6), or (ii) TN conditions and pair-fed (PFTN; n = 6) to eliminate the confounding effects of dissimilar feed intake. A hyperinsulinemic euglycemic clamp (HEC) was conducted on d3 of both periods; and skeletal muscle and adipose tissue biopsies were collected prior to and after an insulin tolerance test (ITT) on d5 of period 2. During the HEC, insulin infusion increased circulating insulin and decreased plasma C-peptide and nonesterified fatty acids, similarly between treatments. From period 1 to 2, the rate of glucose infusion in response to the HEC remained similar in HS pigs while it decreased (36%) in PFTN controls. Prior to the ITT, HS increased (41%) skeletal muscle insulin receptor substrate-1 protein abundance, but did not affect protein kinase B or their phosphorylated forms. In adipose tissue, HS did not alter any of the basal or stimulated measured insulin signaling markers. In summary, HS increases whole-body insulin-stimulated glucose uptake. Published version

Heat stress (HS) compromises a variety of reproductive functions in several mammalian species. Inexplicably, HS animals are frequently hyperinsulinemic despite marked hyperthermia-induced hypophagia. Our objectives were to determine the effects of HS on insulin signaling and components essential to steroid biosynthesis in the pig ovary. Female pigs (35 ± 4 kg) were exposed to constant thermoneutral (20°C; 35%-50% humidity; n = 6) or HS conditions (35°C; 20%-35% humidity; n = 6) for either 7 (n = 10) or 35 days (n = 12). After 7 days, HS increased (P < 0.05) ovarian mRNA abundance of the insulin receptor (INSR), insulin receptor substrate 1 (IRS1), protein kinase B subunit 1 (AKT1), low-density lipoprotein receptor (LDLR), luteinizing hormone receptor (LHCGR), and aromatase (CYP19a). After 35 days, HS increased INSR, IRS1, AKT1, LDLR, LHCGR, CYP19a, and steroidogenic acute regulatory protein (STAR) ovarian mRNA abundance. In addition, after 35 days, HS increased ovarian phosphorylated IRS1 (pIRS1), phosphorylated AKT (pAKT), STAR, and CYP19a protein abundance. Immunostaining analysis revealed similar localization of INSR and pAKT1 in the cytoplasmic membrane and oocyte cytoplasm, respectively, of all stage follicles, and in theca and granulosa cells. Collectively, these results demonstrate that HS alters ovarian insulin-mediated PI3K signaling pathway members, which likely impacts follicle activation and viability. In summary, environmentally induced HS is an endocrine-disrupting exposure that modifies ovarian physiology and potentially compromises production of ovarian hormones essential for fertility and pregnancy maintenance.

Heat stress (HS) jeopardizes human and animal health and reduces animal agriculture productivity; however, its pathophysiology is not well understood. Study objectives were to evaluate the direct effects of HS on carbohydrate and lipid metabolism. Female pigs (57 ± 5 kg body weight) were subjected to two experimental periods. During period 1, all pigs remained in thermoneutral conditions (TN; 20°C) and were ad libitum fed. During period 2, pigs were exposed to: (1) constant HS conditions (32°C) and fed ad libitum (n = 7), or (2) TN conditions and pair-fed (PFTN; n = 10) to minimize the confounding effects of dissimilar feed intake. All pigs received an intravenous glucose tolerance test (GTT) and an epinephrine challenge (EC) in period 1, and during the early and late phases of period 2. After 8 days of environmental exposure, all pigs were killed and tissue samples were collected. Despite a similar reduction in feed intake (39%), HS pigs tended to have decreased circulating nonesterified fatty acids (NEFA; 20%) and a blunted NEFA response (71%) to the EC compared to PFTN pigs. During early exposure, HS increased basal circulating C-peptide (55%) and decreased the insulinogenic index (45%) in response to the GTT. Heat-stressed pigs had a reduced T3 to T4 ratio (56%) and hepatic 5'-deiodinase activity (58%). After 8 days, HS decreased or tended to decrease the expression of genes involved in oxidative phosphorylation in liver and skeletal muscle, and ATGL in adipose tissue. In summary, HS markedly alters both lipid and carbohydrate metabolism independently of nutrient intake. Published version