Heat stress effects on livestock: molecular, cellular

DOI: 10.1111/jpn.12379

REVIEW ARTICLE

Heat stress effects on livestock: molecular, cellular and metabolic aspects, a review I. Belhadj Slimen1,2, T. Najar1,2, A. Ghram3 and M. Abdrrabba2 1 Department of Animal, Food and Halieutic Resources, National Agronomic Institute of Tunisia, Mahragene city, Tunisia 2 Laboratory of Materials, Molecules and Applications, Preparatory Institute for Scientific and Technical Studies, La Marsa, Tunisia, and 3 Laboratory of Microbiology, Pasteur Institute of Tunisia, Mahragene city, Tunisia

Summary Elevated ambient temperatures affect animal production and welfare. Animal’s reduced production performances during heat stress were traditionally thought to result from the decreased feed intake. However, it has recently been shown that heat stress disturbs the steady state concentrations of free radicals, resulting in both cellular and mitochondrial oxidative damage. Indeed, heat stress reorganizes the use of the body resources including fat, protein and energy. Heat stress reduces the metabolic rates and alters post-absorptive metabolism, regardless of the decreased feed intake. Consequently, growth, production, reproduction and health are not priorities any more in the metabolism of heat-stressed animals. The drastic effects of heat stress depend on its duration and severity. This review clearly describes about biochemical, cellular and metabolic changes that occur during thermal stress in farm animals. Keywords heat stress, reactive oxygen species, oxidative stress, insulin, glucose, non-esterified fatty acids Correspondence I. Belhadj Slimen, Department of Animal Science, National Agronomic Institute of Tunisia, 43 Av Charles Nicolle 1082 Tunis, Tunisia. Tel: +216-71-286805; Fax: +216-71-799391; E-mail: [email protected] Received: 26 January 2015; accepted: 12 June 2015

Livestock are subjected to various kinds of stress affecting their production, reproduction and health. Nowadays, environmental-induced heat stress is with major concern because of its detrimental impacts, especially for high-productive animals. In tropical, subtropical and arid regions, high ambient temperature is the major factor jeopardizing animal production. Homoeothermic animals have a thermoneutral zone where normal body temperature is maintained, and energy expenditure is minimal. High ambient temperature, solar radiation and wind speed increase the effective temperature of the environment above the thermoneutral zone of livestock. Therefore, the animal’s body temperature exceeds the range specified for their thermoneutral zone, and the total heat load exceeds the animal’s capacity for heat dissipation (Bernabucci et al., 2010). This situation is called heat stress. When heat stress is accompanied by high ambient humidity, the effect of high temperature is more pro-

nounced because of the reduced heat dissipation by evapotranspiration (Lin et al., 2000; Marai et al., 2007). Heat load increases health problems and mortality rates, especially for high-productive and intolerant animals. In 2006, more than 30 000 dairy cows succumbed in California during a severe heat wave. In Iowa, more than 4000 heads of beef cattle died for the same reason. In Nigeria, heat stress may result in 100% of mortality in broilers (Obeng, 1985). Indeed, chronic heat stress was usually associated with a decreased milk synthesis. A meta-analytic approach was used to evaluate the effect of elevated ambient temperatures on milk production and concluded that the decreased milk yield could result from the cumulative effects of heat stress on feed intake, metabolism and physiology of dairy cattle (Najar et al., 2010). In dairy sheep, selection for increased milk production was shown to reduce heat tolerance (Finocchiaro et al., 2005). Moreover, heat stress was shown to affect negatively animal growth performances in tropical and subtropical regions of the world. Decreased body weight, average daily gain and growth rate were

Journal of Animal Physiology and Animal Nutrition © 2015 Blackwell Verlag GmbH

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Introduction: Effects of hot conditions on livestock production

I. Belhadj Slimen et al.

Heat-induced molecular and metabolic changes in livestock

reported in broilers (Sohail et al., 2010), rabbits (Ayyat and Marai, 1997), lambs (Padua et al., 1997) and beef cattle (Hahn, 1999). A compensatory gain was reported in beef cattle after mild or short period of heat stress (Mader, 2007). Furthermore, heat stress affects most aspects of both male and female reproduction function, such as the pregnancy rate, oestrous activity, embryonic mortality, sperm motility as well as spermatozoa mortality and abnormalities. Several reviews detail the reproductive traits affected by heat stress (Marai et al., 2007; Hansen, 2009). Heat tolerance can be defined as the ability of the animals to maintain the expression of their inherited functional potential when raised under hot conditions. Physiological basis of heat tolerance includes a large skin area to live weight ratio, pigmented skin and eye lids, shielded eyes and a light coloured or white body cover. Environmental heat-tolerant animals should also be able to walk long distances, to adjust to low water intake and to high intake of salts (in drinking water or in forage) as well as poor-quality food (Habeeb et al., 1997). The magnitude of the animal’s response to elevated ambient temperatures is defined by the livestock species and their physiological state. Among livestock species, goats were reported to be the best tolerant to elevated ambient temperatures (Silanikove, 1997, 2000). Similarly, indigenous animals reared in tropical and arid regions are more adapted to hot climate, than those living under temperate environments (Marai et al., 2007). Pregnant and lactating ruminants are more susceptible to heat stress than non-pregnant and non-lactating ones (Silanikove, 1992). Animals selected for high production potential are less tolerant to heat load than animals with low production potential (Najar et al., 2010). Acute and chronic heat stresses exhibit different responses on production and metabolism. Scientists involved in research on heat stress are endeavouring to discover the cellular and molecular responses of heat-stressed animals, and they are also trying to investigate how animals can be managed in hot environments. Investigation of these underlying cellular and molecular processes may provide ways to select heat stress-tolerant animals with high production potential. This study was planned to review the oxidative-induced molecular and cellular responses of animals to high ambient temperature, as well as the metabolic aspects involved in the heat stress response. Understanding these bases may help to handle constraints linked to the decreased animal production.

Molecular responses to heat stress: the oxidative stress

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Heat stress and the antioxidant system

Oxidative stress results from a disturbance in the steady state concentrations of pro-oxidants and antioxidants, leading to overproduction of free radicals and reactive oxygen species (ROS), and a decrease in antioxidant defence (Ganaie et al., 2013). Heat stress was suggested to be responsible of inducing oxidative stress during summer in livestock animals (Ganaie et al., 2013; Nizar et al., 2013). Several studies have concluded that exposure to heat enhances ROS production and induces oxidative stress, which can lead to cytotoxicity (Bernabucci et al., 2002; Lord-Fontaine and Averill-Bates, 2002). Moreover, heat stress was suggested to be similar to oxidative stress, because of correspondences in the genes expressed after heat exposure (such as genes encoding heat-shock proteins and antioxidant enzymes), in comparison with those expressed following oxidant agents’ exposure (Salo et al., 1991). Zuo et al. (2000) and Mujahid et al. (2005) demonstrated the heat-induced increase of ROS production, especially the superoxide anion (O 2 ). Heat stress leads to an overproduction of transition metal ions (TMI) through increasing the rate of iron release from ferritin. TMI can make electron donations to oxygen, forming superoxide anion and/or hydrogen peroxide (H2O2) (Freeman et al., 1990; Powers et al., 1992; Agarwal and Prabhakaran, 2005). As it is highly reactive, O 2 is the precursor of most ROS and a mediator in oxidative chain reactions. H2O2 is further reduced to the extremely reactive hydroxyl radical (OH.) via the Fenton reaction (Liochev and Fridovich, 1999). Fe2þ þ H2 O2 $ Fe3þ + OH þ OH Reactive oxygen species are also generated by the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) while converting NADPH to NADP+ (Segal and Abo, 1993). Heat stress activates NADPH oxidase and increases the NADP+/NADPH ratio (Moon et al., 2010). Further details linking heat stress to oxidative stress were developed by Belhadj Slimen et al. (2014). Uncontrolled increases of ROS concentrations lead to free radical-mediated chain reactions which indiscriminately target proteins (Stadtman and Levine, 2000), lipids (Rubbo et al., 1994), polysaccharides (Kaur and Halliwell, 1994) and deoxyribonucleic acid



(DNA) (LeDoux et al., 1999). In that way, elevated ambient temperatures are associated with increased lipid peroxidation. Thiobarbituric acid-reactive species (TBARS) and malondialdehyde (MDA) are the major products of polyunsaturated fatty acid peroxidation. Environmental heat stress was shown to raise both of TBARS and MDA levels in broilers (Mujahed et al., 2007) as well as buffalos and dairy cows (Kumar et al., 2007; Chandra and Agarwal, 2009; Aengwanich et al., 2011). Heat stress was also shown to increase antioxidant enzymes activities, namely superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), as summarized in Table 1. The increased antioxidant enzymes activities in response to the increased ROS levels aim to maintain the steady state concentrations of generated free radicals. Furthermore, many authors reported that concentrations of endogen antioxidants such as glutathione, vitamins (E, C and A) and ß-carotene decrease during the hot season in multiple animal species (Kumar et al., 2011; Pandey et al., 2012). This decline is explained by the mobilization of cellular antioxidants to detoxify free radicals generated by heat exposure, and to preserve the steady state concentrations of ROS, as explained in Fig. 1. Several studies showed the importance of antioxidant supplementation in alleviating heat stress effects in both in vivo and in vitro trials. Ajakaiye et al. (2011) demonstrated that supplementation with L-ascorbic acid, both singly and in combination with dl-tocopherol acetate, is helpful to heat-stressed layers. Mckeeand and Harrison (2013)showed that administration of ascorbic acid during exposure to high environmental temperatures reduces the body temperature in chickens. Sahin et al. (2003) reported that glutathione

Table 1 Variation of the activity of antioxidant enzymes during the hot season Antioxidant enzymes Superoxide dismutase

Catalase

Glutathione peroxidase

Animals

Activity during summer

Heifers Dairy cows

+++

Buffalo Buffalo Cattle

Cattle Gestating cows

+++

+++

References (Chandra and Agarwal, 2009) (Lallawmkimi, 2009) (Bernabucci et al., 2002) (Megahed et al. (2008)) (Kumar, 2005) (Lallawmkimi, 2009) (Bernabucci et al., 2002) (Lallawmkimi, 2009) (Maan et al., 2013)


DNA

Altered phospholipid bilayer

Lipids

Proteins

+++++

Free radicals

Endogen antioxidants (glutathione, vitamins C, E, A) _ _ _ _ _

Environmental heat stress

Antioxidant enzymes (SOD, CAT, GPX) +++++

Fig. 1 Environmental heat stress and free radicals production. Heat stress increases the production of free radicals. Consequently, endogen antioxidants and antioxidant enzymes are mobilized to scarvenge the produced radicals. If the antioxidant system fails to maintain the steady state concentration of the oxidant species, membranes, lipids, proteins and nucleic acids are altered.

supplementation to heat-stressed broiler chickens improves their performances and decreases the heatinduced antioxidants status. In heat-stressed sheep, selenium injection decreased rectal temperature and body weight loss (Alhidary et al., 2012). Moreover, a thermoprotective role of vitamin E was reported in buffalo cows during the summer (Megahed et al., 2008). Heat-induced mitochondrial damage

Heat stress was qualified as cytotoxic, as it alters biological molecules, disturbs cell functions, modulates metabolic reactions, induces oxidative cell damage and activates both of apoptosis and necrosis pathways (Du et al., 2008; Pandey et al., 2012). Although mitochondria are not the only cellular compartment responsible of ROS production, they ensure the highest part of production. When the steady state concentration of ROS is disturbed, mitochondria are the first cellular compartment to be damaged. In fact, it was shown that the disturbance of the steady state level of ROS production induces the inactivation of the respiratory chain, via the oxidation of complexes I, II, IV and V (England et al., 2004). Hence, the electron flow reduces and the adenosine triphosphate (ATP) synthesis declines (Zhao et al., 2006). As a result, the cellular energy production is downregulated because of the altered oxidative phosphorylation pathway. Indeed, histological abnormalities and altered morphology of mitochondria were denoted in skeletal muscle in a heat-stressed rodent (Hsu et al., 1995; Lewandowska et al., 2006). Besides, the location of mitochondria changed in heat-stressed rats: mitochondria aggregates within the subsarcolemmal space, 3



indicating an increased energy need of the plasma membrane (Hsu et al., 1995). Furthermore, Song et al. (2000) reported alterations in mitochondria structure under heat stress: the mitochondria are swollen, their cristae are broken, and they have a low matrix density. Heat-induced mitochondrial damage may be responsible of cell inability to meet enhanced energy requirements of heat-stressed animals. It was also shown that heat stress results in membrane lipids peroxidation and mitochondrial protein denaturation (Mujahed et al., 2007). Increased free radicals production mediates non-discriminative chain reactions that oxidize mitochondrial proteins and lipids, and constitute a propagation source for free radicals. Moreover, it was reported that heat-induced free radicals production activates the intrinsic pathway of the apoptosis process, which is a mitochondrial pathway based on cytochrome c liberation from the outer mitochondrial membrane (Du et al., 2008). Once liberated, cytochrome c moves to the cytosol and activates initiators and effectors apoptosis proteins, called caspases, resulting in a programmed cell death. Indeed, many authors demonstrated that heat stress induces cell necrosis (Shimizu et al., 1996; Du et al., 2008).

number, as HSPs are induced as a mechanism of cellular defence and/or repair. Cellular responses to heat stress

Although protein synthesis is disturbed under heat stress, this cannot apply to heat-shock proteins (HSPs). HSPs are molecular chaperones differing with their molecular weight and biological function. HSPs can be classified as HSP 110, HSP 100, HSP 90, HSP70, HSP 60, HSP 40, HSP 10, and small HSP families (Feder and Hofmann, 1999). Due to their chaperone function, they ensure the folding, unfolding and refolding of nascent or stress-denatured proteins (Morimoto et al., 1990). HSPs bind to hydrophobic protein sequences liberated by denaturation; thus, they prevent their interaction with neighbour proteins and consequently, the loss of the protein function. Among the cited HSP classes, HSP70 and HSP 90 were correlated with the development of thermotolerance (Hue et al., 2013). In farm animals, heat stress was shown to increase both HSP-70 and HSP-90 in sheep (Romero et al., 2013; Salces-Ortiz et al., 2013), buffalo (Kapila et al., 2013; Kishore et al., 2014), cattle (Deb et al., 2014; Kishore et al., 2014), broilers (Yu et al., 2008) and goats (Dangi et al., 2014). Increased HSP70 and HSP90 levels during heat stress are probably due to the increased damaged proteins

Studies on the cellular effects of heat stress belong to the years 1970 and the early 1980. It was shown that heat stress affects both the fluidity and the stability of cellular membranes and inhibits receptors as well as transmembrane transport proteins function. Heatinduced increase of the fluidity of cellular membranes was observed in thermosensitive cells, in contrast to the thermotolerant ones (Hildebrant et al., 2002). In fact, it was shown that heat stress activates sphingomyelinases (Balogh et al., 2011), phospholipases and phosphatidylinositolphosphate kinases within minutes of ambient temperature increase from 25 to 35 °C and above (Mishkind et al., 2009). This activation triggers the rapid accumulation of phophatidic acid (PA) and phosphatidylinositol 4,5-bisphosphate (PIP2) and their insertion into the plasma membrane and the nuclear envelope (Mishkind et al., 2009). Both PA and PIP2 are signalling lipids (Munnik, 2001; Wang et al., 2006). PIP2 is able to relay upstream signals to effectors that remodel the cell structure and function. Under stress conditions, structural lipids (such as phosphatidylcholine) are hydrolysed to produce PA (Wang, 2005; Bargmann and Munnik, 2006). The cleavage products such as non-esterified fatty acids (NEFA) may be reinserted at different membrane sites causing structural changes and alterations in membrane fluidity (Balogh et al., 2011). As cellular membrane constitutes an important target of heat-induced cell death, this observation allowed to elucidate the variation of membrane potential, the increase of intracellular calcium and sodium levels, as well as the elevation of potassium flux under heat stress conditions (Zhao et al., 2006). Indeed, it was shown that heat stress induces multiple variations in cytoskeleton organization, including the cell form, the mitotic apparatus and the intracytoplasmic membranes such as endoplasmic reticulum and lysosomes. Furthermore, protein synthesis as well as DNA and ribonucleic acid (RNA) polymerization is broken under heat stress. Whereas protein and RNA synthesis recovers rapidly after the heat exposure, DNA synthesis remains inhibited during a longer period (Hahn, 1982; Streffer, 1988). It was also shown that heat stress is not only responsible of protein denaturation, but also it induces their aggregation into the nuclear matrix. This aggregation increases the nuclear protein concentration (Hahn, 1982; Streffer, 1988). Therefore, many

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Heat stress and Heat-shock Proteins


molecular functions are altered, such as DNA synthesis, replication and repair, cellular division and nuclear enzymes and DNA polymerases functions (Higashikubo et al., 1993). Metabolic responses to heat stress Feed intake variation

It was usually thought that animals reduce their feed intake under both acute and chronic heat stresses (Lu et al., 2007). Heat stress upregulates the secretion of two adipokines: leptin and adiponectin, as well as the expression of their receptors (Bernabucci et al., 2009; Morera et al., 2012). Leptin stimulates the hypothalamic axis and results in a reduced feed intake (Rabe et al., 2008). Adiponectin regulates the feeding behaviour through peripheral and central mechanisms, and serves as ‘a starvation signal’ (Hoyda et al., 2012). Hence, heat stress stimulates the hypothalamic axis through increasing leptin and adiponectin levels, and results in a reduced feed intake. This form of caloric restriction allows hyperthermic animals to reduce heat generation. However, the whole effect of heat stress on growth performances cannot be explained only on the basis of the reduced feed intake. Protein metabolism

Heat stress depresses body protein deposition and increases body fat gain (Ain Baziz et al., 1996; Geraert et al., 1996). In broilers, protein deposition is reduced under heat stress (Yunianto et al., 1997). This downregulation of protein synthesis occurs at the transcriptional level, as it has been demonstrated that acute heat stress alters both protein synthesis and ribosomal gene transcription, and results in a lower protein deposition (Jacob, 1995). Furthermore, heat stress depresses RNA content, proteolytic rates and muscle protein turnover (Temim et al., 2000). The duration of heat stress seems to influence differently the protein metabolism of hyperthermic animals (Gonzalez-Esquerra and Leeson, 2005). Short heat stress increases protein catabolism (marked by an increased plasma uric acid level), reduces protein synthesis and N retention, and decreases plasma concentrations of aspartic acid (Asp), serine (Ser), tyrosine (Tyr) and cysteine (Cys) (Tabiri et al., 2000). However, chronic heat exposure knock down protein synthesis in various muscles, decreases protein breakdown, with lower levels of plasma amino acids (especially sulphur and branched-chain amino acids) and higher serum levels of Asp, glutamic acid (Glu) Journal of Animal Physiology and Animal Nutrition © 2015 Blackwell Verlag GmbH


and phenylalanine (Phe) (Geraert et al., 1996; Temim et al., 2000). Moreover, high-fat and energy diets allowed a greater fat deposition in hyperthermic animals, than high-protein diets (Le Bellego et al., 2002). Heat stress seems to affect the distribution of energy between fat and protein deposition, although the gross energy cost of depositing 1 g of protein was calculated at 8.7 Kcal/ g, and the gross energy cost of depositing 1 g of lipid was evaluated at 12.0 Kcal/g (Millward et al., 1976). Increased protein catabolism under chronic heat stress is likely to produce glucose through the gluconeogenesis pathway. Lipid metabolism

Lipid metabolism is affected by chronic heat stress. Ambient temperature-induced heat stress was shown to reduce fat oxidation in different species. Several studies demonstrated that during heat stress, basal levels of NEFA are typically reduced in rodents (Sanders et al., 2009), pigs (Pearce et al., 2011) and dairy cows (Shwartz et al., 2009). This reduction is independent from the reduced dry matter intake. Moreover, heat stress downregulates lipolytic enzyme activities, as seen in chickens and swine (Geraert et al., 1996). The blunted lipolytic activity of the adipose tissue seems to be an adaptation form to limit heat generation in heat-stressed animals. Although lipolytic enzyme activity is reduced under heat stress, the activity of the lipoprotein lipase of the adipose tissue is increased, which allows suggesting that hyperthermic animals have a greater storage capacity of intestinal and hepatic triglycerides (Sanders et al., 2009). Bibliographic data reported that rodents (Katsumata et al., 1990), broilers (Geraert et al., 1996) and growing poultry (Lu et al., 2007) have a greater fat deposition when reared under heat stress conditions. Fat deposition in hyperthermic animals depends on the breed. In chickens, Lu et al. (2007) demonstrated that heat stress affects fat deposition in a breed-dependent manner. According to this study, the heat-tolerant breed had lesser abdominal fat deposition. Other studies are necessary to evaluate the relation between fat deposition and heat tolerance. Carbohydrate metabolism

Carbohydrates are a readily available energy source that can be converted into a number of metabolic intermediates and used in synthesis reactions, or utilized for the production of ATP. ATP generation is a 5



highly regulated process involving three distinct pathways generally termed glycolysis, the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (via the electron chain transport). Pathway regulation is determined by several mechanisms affecting enzyme activity including synthesis and degradation rates, allosteric interactions and covalent modification, and the energy charge of the cell (Berg et al., 2007). Blood glucose levels are affected by the severity and the duration of heat stress. Acute heat stress does not affect glucose concentration in broilers (Lin et al., 2000) and rats (Miova et al., 2013). Saunders et al. (2001) reported that mild heat stress increased significantly intramuscular glycogen phosphorylase and pyruvate dehydrogenase activity, without affecting the intramuscular concentrations of glucose 6-phosphate, lactate, pyruvate, acetyl-coenzyme A (acetylCoA), creatine, phosphocreatine or ATP. Chronic heat stress decreases circulating glucose levels in Holstein bull calves (O’Brien et al., 2010), cows (Settivari et al., 2007), heifers (Itoh et al., 1998), sheep (Achmadi et al., 1993) and broilers (Lin et al., 2000). This decline was observed in spite of the increase of the intestinal glucose absorptive capacity (Garriga et al., 2006), the elevation of the renal glucose reabsorptive capacity (Ikari et al., 2005), and the enhanced hepatic glucose output (Febbraio, 2001). The increased glucose pool entry coupled with the decreased blood glucose may suggest a higher rate of glucose leaving the circulating blood pool. Hence, glucose becomes the favoured fuel of heat-stressed animals. Due to the increased reduction of fatty acid oxidation under chronic heat stress, heat-stressed animals become increasingly dependent on glucose for their energy needs. Taking into account the decreased feed intake and blood glucose levels, the use of glucose to meet production variables (lactation and growth) is declined (Baumgard and Rhoads, 2007). Therefore, heat-stressed cows (Moore et al., 2005), broilers (Simmons et al., 1997) and rabbits (Szendr} o, 2008) enter into a state of negative energy balance.

Chronic heat stress increases skeletal muscle abundance of PDK4 in rodents, pigs and ruminants (O’Brien et al., 2008; Rhoads et al., 2011; Won et al., 2012). Moreover, Streffer (1988) reported that ratios of lactate/pyruvate and NADH/NAD+ increase during heat stress. These data indicate that the pyruvate entry into the TCA cycle through the pyruvate dehydrogenase complex (PDH complex) is altered by heat stress. This inactivation of PDH complex may result from oxidative chain reactions generated by intracellular ROS. The oxidative phosphorylation

Mitochondrial ATP synthesis is impaired under heat stress through the electron transport chain dysfunction. It was reported that heat stress inactivates complex I of the electron transport chain (ETC.) and results in its dissociation into smaller components (Downs and Heckathorn, 1998). In addition, it was shown that ROS oxidizes protein thiols of complexes I, II, IV and V (F0F1 – ATPase) (England et al., 2004) and carbonylates several glycolytic enzymes (Colussi et al., 2000). Besides, ROS-activated poly(ADP-ribose) polymerase reduces both NAD+ and ATP (Troyano et al., 2003). As a result, the oxygen uptake by the respiratory chain reduces and causes the decrease of electron flow along the respiratory chain, and therefore the depletion of ATP syntheses (Pobezhimova et al., 1996). The glycogenolysis, the gluconeogenesis and the Cori cycle pathways

Chronic and acute heat stresses alter differently the TCA cycle. Short-term acute heat stress was shown to accelerate the TCA cycle (Gandhi et al., 2011), increase the skeletal muscle abundance of mRNA of both pyruvate dehydrogenase kinase 4 (PDK4) and lactate dehydrogenase kinase (LDH) (Sanders et al., 2009), and decrease urinary excretion levels of succinate, citrate and 2-oxoglutarate (Gandhi et al., 2011).

The prevention/reduction of heat load is associated with reduced muscle glycogenolytic rate and/or carbohydrates oxidation (Gonzalez-Alonso et al., 1999). Hargreaves et al. (1996) reported that glycogen breakdown is accelerated during exercise in hot environment. These data suggest that glycogen utilization is enhanced during heat stress, which may be due to increased/enhanced anaerobic metabolism. The exogenous sugars supplementation reduces hepatic glucose production, but do not blunt the heat-induced liver glucose output (Angus et al., 2001). These findings indicate the increased rate of glycogenolysis and gluconeogenesis under chronic heat stress (Febbraio, 2001; Miova et al., 2013). Similarly, acute heat stress results in an enhanced glycogenolysis but a decreased gluconeogenesis (Miova et al., 2013). Interestingly, Wheelock et al. (2008) and O’Brien et al. (2008) reported that hepatic expression of the pyruvate carboxylase gene increases under chronic heat stress. Pyruvate carboxylase is a rate-limiting enzyme that regulates the entry of alanine and lactate into the gluconeogenesis pathway. Several authors

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The TCA cycle



reported increased blood lactate concentrations in different heat-stressed models (Streffer, 1988; Elsasser et al., 2009; Baumgard and Rhoads, 2013). These observations agree with Streffer (1988) who reported that ratios of lactate/pyruvate and NADH/NAD+ are elevated during heat stress. These data allow to concluding that lactate is used as an alternative fuel to produce glucose via the Cori cycle, perhaps to ensure glucose requirements of tissues that are obligate glucose users. Hyperinsulinaemia

Insulin is a potent regulator of carbohydrate and lipid metabolism, and plays an important role in mediating the regulation the post-absorptive nutrient partitioning in heat-stressed animals. Although acute heat stress was shown to decrease insulin concentrations in broilers (Tang et al., 2013), chronic heat stress was shown to increase insulin levels in rodents (Morera et al., 2012), pigs (Pearce et al., 2011), lactating cows (Wheelock et al., 2010), growing calves (O’Brien et al., 2010), sheep (Achmadi et al., 1993) and broilers (Yuan et al., 2008). Increased insulin receptor abundance was reported by Tech et al. (2014) in heat-stressed cows. Increased insulin blood level during chronic heat stress explains the decreased circulating glucose concentration, the blunted lipolytic activity and the increased lipogenesis of adipose tissue. This increase in insulin sensitivity is suggested to be an adaptive mechanism used to decrease heat production, as oxidizing glucose is more efficient (Baldwin et al., 1980) and yields to 38 ATP or 472.3 Kcal of energy, whereas in vivo fatty acid oxidation (i.e. stearic acid) generates 146 ATP or 1814 Kcal of energy (Berg et al., 2007). However, the mechanisms regulating insulin secretion during heat stress remain unclear.

as maize, may exacerbate the problem, because it increases the heat load through the digestion of the energy source. Alternatively, feeding dietary fat (rumen inert/rumen bypass) was shown to reduce rectal temperature and to increase milk yield in dairy cows (Wang et al., 2010). Compared to starch and fibre, fat has a much lower heat increment in the rumen. Reducing carbohydrate levels will allow higher ammonia levels in the rumen, thus higher degradable proteins and soluble nitrogen sources. Indeed, milk production can be maintained under hot climatic conditions by increasing rumen production of glucose precursors. Monensin (Baumgard et al., 2011), glycerol (Boyd et al., 2010) and propylene glycol (Tunon et al., 2004) can be used to maximize rumen propionate production. In broilers, the adverse effects of heat stress can be alleviating by supplementation with fatty acids (Mujahid et al., 2009). Moreover, feeding high-protein diet was shown to improve body weight gain, feed conversion ratio and muscle protein gain in broilers (Temim et al., 2000; Gonzalez-Esquerra and Leeson, 2005). In cows, feeding more bypass protein during the heat stress period may enhance milk production (Terada, 1996).

Conclusion Heat-stressed animals initiate a caloric restriction to minimize heat and ROS production. Although these survival strategies reduce productivity and severely alter farm economics, post-absorptive metabolic changes seem to be adaptive mechanisms used to maintain euthermia. Hence, nutritional strategies are needed to help animals to reduce metabolic heat generation and to maintain their production performances during thermal stress.

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Conflict of interest The authors declare no conflict of interest.

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