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Originally named for its expression in the posterior hypothalamus in rats and after the Greek word for “appetite”, hypocretin, or orexin, as it is known today, gained notoriety as a neuropeptide regulating feeding behavior, energy homeostasis, and sleep. Orexin has been proven to be involved in both central and peripheral control of neuroendocrine functions, energy balance, and metabolism. Since its discovery, its ability to increase appetite as well as regulate feeding behavior has been widely explored in mammalian food production animals such as cattle, pigs, and sheep. It is also linked to neurological disorders, leading to its intensive investigation in humans regarding narcolepsy, depression, and Alzheimer’s disease. However, in non-mammalian species, research is limited. In the case of avian species, orexin has been shown to have no central effect on feed-intake, however it was found to be involved in muscle energy metabolism and hepatic lipogenesis. This review provides current knowledge and summarizes orexin’s physiological roles in livestock and pinpoints the present lacuna to facilitate further investigations.

Complex disease states, like bacterial chondronecrosis with osteomyelitis (BCO), not only result in physiological symptoms, such as lameness, but also a complex systemic reaction involving immune and growth factor responses. For the modern broiler (meat-type) chickens, BCO is an animal welfare, production, and economic concern involving bacterial infection, inflammation, and bone attrition with a poorly defined etiology. It is, therefore, critical to define the key inflammatory and bone-related factors involved in BCO. In this study, the local bone and systemic blood profile of inflammatory modulators, cytokines, and chemokines was elucidated along with inflammasome and key FGF genes. BCO-affected bone showed increased expression of cytokines IL-1β, while BCO-affected blood expressed upregulated TNFα and IL-12. The chemokine profile revealed increased IL-8 expression in both BCO-affected bone and blood in addition to inflammasome NLRC5 being upregulated in circulation. The key FGF receptor, FGFR1, was significantly downregulated in BCO-affected bone. The exposure of two different bone cell types, hFOB and chicken primary chondrocytes, to plasma from BCO-affected birds, as well as recombinant TNFα, resulted in significantly decreased cell viability. These results demonstrate an expression of proinflammatory and bone-resorptive factors and their potential contribution to BCO etiology through their impact on bone cell viability. This unique profile could be used for improved non-invasive detection of BCO and provides potential targets for treatments.

Bacterial Chondronecrosis with Osteomyelitis (BCO) is a specific cause of lameness in commercial fast-growing broiler (meat-type) chickens and represents significant economic, health, and wellbeing burdens. However, the molecular mechanisms underlying the pathogenesis remain poorly understood. This study represents the first comprehensive characterization of the proximal tibia proteome from healthy and BCO chickens. Among a total of 547 proteins identified, 222 were differentially expressed (DE) with 158 up- and 64 down-regulated proteins in tibia of BCO vs. normal chickens. Biological function analysis using Ingenuity Pathways showed that the DE proteins were associated with a variety of diseases including cell death, organismal injury, skeletal and muscular disorder, immunological and inflammatory diseases. Canonical pathway and protein–protein interaction network analysis indicated that these DE proteins were involved in stress response, unfolded protein response, ribosomal protein dysfunction, and actin cytoskeleton signaling. Further, we identified proteins involved in bone resorption (osteoclast-stimulating factor 1, OSFT1) and bone structural integrity (collagen alpha-2 (I) chain, COL2A1), as potential key proteins involved in bone attrition. These results provide new insights by identifying key protein candidates involved in BCO and will have significant impact in understanding BCO pathogenesis.

Heat stress (HS) is one of the most challenging stressors to poultry production sustainability. The adverse effects of HS range from feed intake and growth depression to alteration of meat quality and safety. As phytase supplementation is known to improve nutrient utilization and consequently growth, we undertook the present study to evaluate the effects of dietary phytase on growth and meat quality in heat-stressed broilers. A total of 720 day-old hatch Cobb 500 chicks were assigned to 24 pens within controlled environmental chambers and fed three diets: Negative Control (NC), Positive Control (PC), and NC diet supplemented with 2000 phytase units (FTU)/kg) of quantum blue (QB). On day 29, birds were exposed to two environmental conditions: thermoneutral (TN, 25 °C) or cyclic heat stress (HS, 35 °C, 8 h/d from 9 a.m. to 5 p.m.) in a 3 × 2 factorial design. Feed intake (FI), water consumption (WI), body weight (BW), and mortality were recorded. On day 42, birds were processed, carcass parts were weighed, and meat quality was assessed. Breast tissues were collected for determining the expression of target genes by real-time quantitative PCR using the 2−ΔΔCt method. HS significantly increased core body temperature, reduced feed intake and BW, increased water intake (WI), elevated blood parameters (pH, SO2, and iCa), and decreased blood pCO2. HS reduced the incidence of woody breast (WB) and white striping (WS), significantly decreased drip loss, and increased both 4- and 24-h postmortem pH. Instrumental L* and b* values were reduced (p < 0.05) by the environmental temperature at both 4- and 24-h postmortem. QB supplementation reduced birds’ core body temperature induced by HS and improved the FCR and water conversion ratio (WCR) by 1- and 0.5-point, respectively, compared to PC under HS. QB increased blood SO2 and reduced the severity of WB and WS under TN conditions, but it increased it under an HS environment. The abovementioned effects were probably mediated through the modulation of monocarboxylate transporter 1, heat shock protein 70, mitogen-activated protein kinase, and/or glutathione peroxidase 1 gene expression, however, further mechanistic studies are warranted. In summary, QB supplementation improved growth performance and reduced muscle myopathy incidence under TN conditions. Under HS conditions, however, QB improved growth performance but increased the incidence of muscle myopathies. Therefore, further QB titration studies are needed.

Powered by consumer taste, value, and preferences, natural products including phytogenics and algae are increasingly and separately used in the food systems where they have been reported to improve growth performance in poultry and livestock. The present study aimed to determine the effects of a new feed additive, microencapsulated NUQO© NEX, which contains a combination of phytogenic and phycogenic, on broiler growth performance, blood chemistry, bone health, meat quality and sensory profile. Male Cobb500 chicks ( n  = 1,197) were fed a 3-phase feeding intervals; 1–14d starter, 15–28d grower, and 29–40d finisher. The dietary treatments included a corn-soy basal Control (CON), basal diet supplemented with NUQO© NEX at 100 g/ton from 1 to 28d then 75 g/ton from d 28 to 40 (NEX75), and basal diet supplemented with NUQO© NEX at 100 g/ton from 1 to 40d (NEX100). The NEX100 supplemented birds had 62 g more BWG increase and 2.1-point improvement in FCR compared with CON in the finisher and overall growth phase ( p  < 0.05), respectively. Day 40 processing body weights and carcass weights were heavier for the NEX100 supplemented birds ( p  < 0.05). The incidences of muscle myopathies were also higher in NEX treatments, which could be associated with the heavier weights, but the differences were not detected to be significant. The NEX75 breast filets had more yellowness than other dietary treatments ( p  = 0.003) and the NEX 100 treatment reduced the levels of breast filet TBARS at 7 days-post harvest ( p  = 0.053). Finally, both NEX treatments reduced the incidence of severe bone (tibia and femur) lesions. In conclusion, the supplementation of the phytogenic NUQO© NEX improved finisher performance parameters, whole phase FCR, processing carcass weights, and breast filet yellowness, at varying inclusion levels.

Heat stress (HS) is devastating to poultry production sustainability worldwide. In addition to its adverse effects on growth, welfare, meat quality, and mortality, HS alters the gut integrity, leading to dysbiosis and leaky gut syndrome; however, the underlying mechanisms are not fully defined. Here, we used a high-throughput mass spectrometric metabolomics approach to probe the metabolite profile in the duodenum of modern broilers exposed to acute (AHS, 2 h) or chronic cyclic (CHS, 8 h/day for 2 weeks) HS in comparison with thermoneutral (TN) and pair-fed birds. Ultra high performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC–HRMS) identified a total of 178 known metabolites. The trajectory analysis of the principal component analysis (PCA) score plots (both 2D and 3D maps) showed clear separation between TN and each treated group, indicating a unique duodenal metabolite profile in HS birds. Within the HS groups, partial least squares discriminant analysis (PLS-DA) displayed different clusters when comparing metabolite profiles from AHS and CHS birds, suggesting that the metabolite signatures were also dependent on HS duration. To gain biologically related molecule networks, the above identified duodenal metabolites were mapped into the Ingenuity Pathway Analysis (IPA) knowledge-base and analyzed to outline the most enriched biological functions. Several common and specific top canonical pathways were generated. Specifically, the adenosine nucleotide degradation and dopamine degradation pathways were specific for the AHS group; however, the UDP-D-xylose and UDP-D-glucuronate biosynthesis pathways were generated only for the CHS group. The top diseases enriched by the IPA core analysis for the DA metabolites, including cancer, organismal (GI) injury, hematological, cardiovascular, developmental, hereditary, and neurological disorders, were group-specific. The top altered molecular and cellular functions were amino acid metabolism, molecular transport, small molecule biochemistry, protein synthesis, cell death and survival, and DNA damage and repair. The IPA-causal network predicted that the upstream regulators (carnitine palmitoyltransferase 1B, CPT1B; histone deacetylase 11, HDAC11; carbonic anhydrase 9, CA9; interleukin 37, IL37; glycine N-methyl transferase, GNMT; GATA4) and the downstream mediators (mitogen-activated protein kinases, MAPKs; superoxide dismutase, SOD) were altered in the HS groups. Taken together, these data showed that, independently of feed intake depression, HS induced significant changes in the duodenal metabolite profile in a duration-dependent manner and identified a potential duodenal signature for HS.

Femur head necrosis (FHN), also known as bacterial chondronecrosis with osteomyelitis (BCO), has remained an animal welfare and production concern for modern broilers regardless of efforts to select against it in primary breeder flocks. Characterized by the bacterial infection of weak bone, FHN has been found in birds without clinical lameness and remains only detectable via necropsy. This presents an opportunity to utilize untargeted metabolomics to elucidate potential non-invasive biomarkers and key causative pathways involved in FHN pathology. The current study used ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC–HRMS) and identified a total of 152 metabolites. Mean intensity differences at p < 0.05 were found in 44 metabolites, with 3 significantly down-regulated and 41 up-regulated in FHN-affected bone. Multivariate analysis and a partial least squares discriminant analysis (PLS-DA) scores plot showed the distinct clustering of metabolite profiles from FHN-affected vs. normal bone. Biologically related molecular networks were predicted using an ingenuity pathway analysis (IPA) knowledge base. Using a fold-change cut off of −1.5 and 1.5, top canonical pathways, networks, diseases, molecular functions, and upstream regulators were generated using the 44 differentially abundant metabolites. The results showed the metabolites NAD+, NADP+, and NADH to be downregulated, while 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) and histamine were significantly increased in FHN. Ascorbate recycling and purine nucleotides degradation were the top canonical pathways, indicating the potential dysregulation of redox homeostasis and osteogenesis. Lipid metabolism and cellular growth and proliferation were some of the top molecular functions predicted based on the metabolite profile in FHN-affected bone. Network analysis showed significant overlap across metabolites and predicted upstream and downstream complexes, including AMP-activated protein kinase (AMPK), insulin, collagen type IV, mitochondrial complex, c-Jun N-terminal kinase (Jnk), extracellular signal-regulated kinase (ERK), and 3β-hydroxysteroid dehydrogenase (3β HSD). The qPCR analysis of relevant factors showed a significant decrease in AMPKα2 mRNA expression in FHN-affected bone, supporting the predicted downregulation found in the IPA network analysis. Taken as a whole, these results demonstrate a shift in energy production, bone homeostasis, and bone cell differentiation that is distinct in FHN-affected bone, with implications for how metabolites drive the pathology of FHN.

Heat stress (HS) is devastating to poultry production sustainability due its detrimental effects on performance, welfare, meat quality, and profitability. One of the most known negative effects of HS is feed intake depression, which is more pronounced in modern high-performing broilers compared to their ancestor unselected birds, yet the underlying molecular mechanisms are not fully defined. The present study aimed, therefore, to determine the hypothalamic expression of a newly involved pathway, hypoxia/oxygen homeostasis, in heat-stressed broiler-based research lines and jungle fowl. Three populations of broilers (slow growing ACRB developed in 1956, moderate growing 95RB from broilers available in 1995, and modern fast growing MRB from 2015) and unselected Jungle fowl birds were exposed to cyclic heat stress (36°C, 9 h/day for 4 weeks) in a 2 × 4 factorial experimental design. Total RNAs and proteins were extracted from the hypothalamic tissues and the expression of target genes and proteins was determined by real-time quantitative PCR and Western blot, respectively. It has been previously shown that HS increased core body temperature and decreased feed intake in 95RB and MRB, but not in ACRB or JF. HS exposure did not affect the hypothalamic expression of HIF complex, however there was a line effect for HIF-1α ( P = 0.02) with higher expression in JF under heat stress. HS significantly up regulated the hypothalamic expression of hemoglobin subunits (HBA1, HBBR, HBE, HBZ), and HJV in ACRB, HBA1 and HJV in 95RB and MRB, and HJV in JF, but it down regulated FPN1 in JF. Additionally, HS altered the hypothalamic expression of oxygen homeostasis- up and down-stream signaling cascades. Phospho-AMPK Thr172 was activated by HS in JF hypothalamus, but it decreased in that of the broiler-based research lines. Under thermoneutral conditions, p-AMPK Thr172 was higher in broiler-based research lines compared to JF. Ribosomal protein S6K1, however, was significantly upregulated in 95RB and MRB under both environmental conditions. HS significantly upregulated the hypothalamic expression of NF-κB2 in MRB, RelB, and TNFα in ACRB, abut it down regulated RelA in 95RB. The regulation of HSPs by HS seems to be family- and line-dependent. HS upregulated the hypothalamic expression of HSP60 in ACRB and 95RB, down regulated HSP90 in JF only, and decreased HSP70 in all studied lines. Taken together, this is the first report showing that HS modulated the hypothalamic expression of hypoxia- and oxygen homeostasis-associated genes as well as their up- and down-stream mediators in chickens, and suggests that hypoxia, thermotolerance, and feed intake are interconnected, which merit further in-depth investigations.

Bacterial chondronecrosis with osteomyelitis (BCO), a leading cause of lameness in broiler chickens, is characterized by infection, inflammation, and bone attrition. There are currently no effective treatments and positive diagnosis is only possible through necropsy evaluations. Lameness is also a rising animal welfare and economic concern, making prevention anddetection of BCO all the more critical. These challenges are exacerbated by a lack of mechanistic understanding of BCO’s etiology. The question I asked during my dissertation was how bacteria induce bone attrition in BCO pathology. My research has shown that mitochondrial dysfunction is characteristic of BCO conditions along with autophagy machinery dysregulation. This autophagy dysregulation is also seen to a result of in vitro infection with known BCO-isolates and affecting bone cell viability. The local bone and systemic blood profile of cytokines, chemokines, inflammasomes, and relevant FGFs were also evaluated. This revealed a unique signature of BCO detectable within circulation and in local bone. Additionally, this signature was made up of factors which negatively affect bone cell viability. It was also shown that primary avian chondrocytes exhibiting optimal phenotypes could be successfully isolated form chicks. These primary cells could provide an improved, highly relevant model for in vitro analysis of avian bone diseases and infections. Finally, the potential roles of two factors regulating energy and lipid metabolism were preliminarily explored as a future target for BCO research. These findings provide novel insight into mechanisms of etiology and means of non-invasive detection while also improving upon current methods of avian growth-plate research

Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.