Whole-body oxidation of fuels and feeding

The effect of fuel oxidation on food intake in laboratory species has been reviewed in detail previously (Langhans, Reference Langhans1996; Friedman, Reference Friedman1998). Various metabolic inhibitors have been reported to stimulate feeding by inhibiting the oxidation of glucose or fatty acids (FA). Food intake by laboratory species has been stimulated by the inhibition of glycolysis by 2-deoxy-d-glucose (Novin et al., Reference Novin, VanderWeele and Rezek1973), pyruvate transport across the mitochondrial membrane by α-cyano-4-hydroxycinnamic acid (Del Prete et al., Reference Del Prete, Lutz and Scharrer2004), long-chain FA transport across the mitochondrial membrane by methyl palmoxirate (Friedman and Tordoff, Reference Friedman and Tordoff1986) and etomoxir (Horn et al., Reference Horn, Ji and Friedman2004), and β-oxidation by mercaptoacetate (Scharrer and Langhans, Reference Scharrer and Langhans1986). In addition, food intake was decreased by the stimulation of fuel oxidation by PPARγ agonists in rats (Fu et al., Reference Fu, Gaetani, Oveisi, Lo Verme, Serrano, Rodríguez De Fonseca, Rosengarth, Luecke, Di Giacomo, Tarzia and Piomelli2003, Reference Fu, Oveisi, Gaetani, Lin and Piomelli2005) and by knockdown of 11β-hydroxysteroid dehydrogenase type 1 in mice (Li et al., Reference Li, Hernandez-Ono, Crooke, Graham and Ginsberg2011). Synergistic effects of inhibiting glucose and FA oxidation on food intake have been reported; inhibition of glycolysis by 2-deoxyglucose and FA oxidation by methyl palmoxirate synergistically increased feeding in rats (Friedman and Tordoff, Reference Friedman and Tordoff1986), as did inhibition of glycolysis by 2-deoxyglucose and lipolysis by nicotinic acid (Friedman et al., 1986). Furthermore, feeding events were related to periprandial patterns of fat and carbohydrate oxidation measured by respiration calorimetry in lactating cows (Derno et al., Reference Derno, Nurnberg, Schon, Schwarm, Rontgen, Hammon, Metges, Bruckmaier and Kuhla2013).

Control of feed intake by hepatic oxidation

Extensive evidence with laboratory species suggests that the liver provides a common integrated mechanism for the control of feeding behavior by the oxidation of a variety of fuels (Forbes, Reference Forbes1988; Langhans, Reference Langhans1996; Friedman, Reference Friedman1998; Scharrer, Reference Scharrer1999). The hepatic oxidation theory (HOT) of the control of feed intake has been applied to ruminant animals (Allen et al., Reference Allen, Bradford and Oba2009; Allen and Bradford, Reference Allen and Bradford2012; Allen, Reference Allen2014) and will be briefly summarized here. Signals from the liver are transmitted to brain feeding centers via vagal afferents (Anil and Forbes, Reference Anil and Forbes1988). The signal from the liver may be both inhibitory (affecting satiety) and stimulatory (affecting hunger) and is related to hepatic oxidation of fuels (Friedman, Reference Friedman1997). Feeding behavior is affected by the firing rate of the nerve; increased oxidation decreases the firing rate, inhibiting feeding, whereas decreased oxidation increases the firing rate, stimulating feeding (Friedman, Reference Friedman1997). Fuels extracted from the blood by the liver can be converted to acetyl CoA (AcCoA) and oxidized in the tricarboxylic acid (TCA) cycle. Hepatic oxidation varies over minutes affecting feeding behavior and is dependent upon the supply of AcCoA and the capacity of the TCA cycle.

Fuels oxidized by the ruminant liver

Fuel supply to the liver is dependent upon the absorption of fuels derived from the diet as well as those supplied by or extracted from the blood by extrahepatic tissues (Figure 1). Fuels extracted from the blood and oxidized in ruminant liver include non-esterified fatty acids (NEFA), amino acids (AA), lactate, glycerol, short-chain FA (except acetate) and medium-chain FA. Little acetate, if any, is extracted from the blood because of low activity of AcCoA synthetase (Ricks and Cook, Reference Ricks and Cook1981) necessary for its conversion to AcCoA and subsequent metabolism. In addition, little glucose is extracted from the blood of mature ruminants that lack glucokinase (Ballard, Reference Ballard1965), ensuring low hepatic glycolysis (Aschenbach et al., Reference Aschenbach, Kristensen, Donkin, Hammon and Penner2010). All fuels must be converted to AcCoA in the mitochondria for complete oxidation to CO₂ in the TCA cycle. Fatty acids are converted to AcCoA by β-oxidation, whereas glucogenic fuels are converted to AcCoA through pyruvate by the pyruvate dehydrogenase complex, and ketogenic AA are converted directly to AcCoA after deamination. Although propionate and other glucose precursors can be converted to pyruvate when their supply exceeds the glucogenic flux, conversion of pyruvate to AcCoA is likely inhibited in the postpartum period. Elevated concentrations of AcCoA activate pyruvate carboxylase if energy charge is high (Petersen et al., Reference Petersen, Cline, Blair and Shulman1994) and inhibits conversion of pyruvate to AcCoA by the pyruvate dehydrogenase complex (Begum et al., Reference Begum, Tepperman and Tepperman1983), providing negative feedback and conserving TCA intermediates.

Figure 1

Flow of potential metabolic fuels in ruminant animals. (1) Short-chain fatty acids (FA) produced by ruminal fermentation (e.g. acetate, propionate, butyrate, etc.) as well as glucose, lactate, amino acids, and medium-chain FA flow to the liver from the portal-drained viscera. The type and temporal absorption of potential fuels is dependent upon diet composition and digestion kinetics affecting the site of digestion. Extraction by the liver varies by fuel and over time depending upon enzyme activities and redox state of the liver. Little glucose and acetate are extracted by ruminant liver, sparing them for use by extrahepatic tissues. Propionate extraction from portal blood is high, but extraction of other fuels is lower and variable. (2) Long-chain FA are absorbed in the lymphatic system. (3) Fuels released from the liver include glucose, β-hydroxybutyrate (BHB), acetate, amino acids (AA) and very-low-density lipoproteins. Fuels extracted by the liver from circulating blood include non-esterified FA (NEFA), glycerol, lactate and AA. When AA are supplied in excess, and when AA profile diverges from optimal, their oxidation and use for anaplerosis increases. Glucose output by the liver into the blood is affected by its demand by tissues and controlled primarily by insulin and glucagon. (4) Milk synthesis by the mammary gland is a sink for potential fuels, including glucose, NEFA, acetate, butyrate and AA. Removal of these fuels from the blood likely promotes intake by reducing their availability for oxidation in the liver. (5) Adipose tissue extracts acetate, glucose and NEFA from the blood during lipogenesis and mobilizes triacylglycerol, increasing the availability of NEFA and glycerol for hepatic oxidation. (6) Muscle tissue utilizes glucose, acetate, glycerol, BHB and NEFA as fuels, and AA for protein synthesis. Amino acids are mobilized during negative energy balance, increasing their availability as fuels following deamination, although anaplerosis of glucogenic AA decreases their oxidation compared with ketogenic AA. Lactate from partial metabolism of glucose by the muscle is available for gluconeogenesis or oxidation in the liver (adapted from Allen, Reference Allen2014 with permission).

Control of hepatic oxidation

Hepatic oxidation of fuels fluctuates with the energy needs of the liver, which varies over weeks and months (e.g. to support growth and lactation; Reynolds et al., Reference Reynolds, Dürst, Lupoli, Humphries and Beever2004). However, the periprandial pattern of fuel oxidation affects hepatic energy status and is involved in the control of feeding behavior (Friedman, Reference Friedman1997). Energy status of the liver is dependent upon the balance between energy-consuming and energy-producing reactions. Acetyl CoA enters the TCA cycle for oxidation but can also be used for anabolic pathways or exported from the liver as ketone bodies or hydrolyzed and released as acetate (Allen et al., Reference Allen, Bradford and Oba2009). The entry of AcCoA into the TCA cycle requires oxaloacetate (OAA) for the citrate synthase reaction. The availability of OAA is dependent upon the concentration of TCA intermediates and the rate of reactions within the TCA cycle (Allen, Reference Allen2014). The concentration of TCA intermediates in the mitochondria of hepatocytes is determined by the balance between anaplerosis (entry into the cycle) and cataplerosis (exit from the cycle). Intermediates exit the TCA cycle as they are used in biosynthetic pathways. Pre-gastric fermentation limits glucose available for absorption, so glucose needs are met by gluconeogenesis, which is the primary factor affecting cataplerosis in ruminants (Aschenbach et al., Reference Aschenbach, Kristensen, Donkin, Hammon and Penner2010). Anaplerotic metabolites include propionate, glucogenic AA, lactate and glycerol (Aschenbach et al., Reference Aschenbach, Kristensen, Donkin, Hammon and Penner2010). Propionate carbon enters the TCA cycle as succinyl CoA, and other metabolites enter the TCA cycle at other sites (i.e. OAA and α-ketoglutarate). The speed at which they are able to stimulate the oxidation of AcCoA is dependent upon the concentrations of enzymes and cofactors, enzyme activity and end-product accumulation of individual reactions (Allen, Reference Allen2014). Elevated [NADH]/[NAD] and [ATP] indicate energy sufficiency, decreasing the rate of certain reactions and the availability of OAA for the citrate synthase reaction (Allen et al., Reference Allen, Bradford and Oba2009).

Modulation of hepatic oxidation

Hormones and cytokines modulate hepatic oxidation over both the long and short terms by affecting the availability of AcCoA for oxidation, as well as anaplerosis and cataplerosis of TCA cycle intermediates. This section reviews the major factors modulating hepatic oxidation, including insulin, glucagon, somatotropin and leptin.

Plasma concentration of insulin varies over the long term with elevated concentrations indicating energy adequacy. Insulin is secreted by the pancreas in response to glucose as well as propionate and butyrate (Manns and Boda, Reference Manns and Boda1967). Other nutrients such as NEFA and certain AA can augment glucose-induced insulin secretion (Fu et al., Reference Fu, Gilbert and Liu2013). In addition, insulin secretion is regulated by various hormones, including melatonin, estrogen, leptin, somatotropin and glucagon like peptide-1 (Fu et al., Reference Fu, Gilbert and Liu2013). Insulin suppresses gluconeogenesis and ketogenesis in the liver (Brockman and Laarveld, Reference Brockman and Laarveld1986), modulating hepatic oxidation by reducing cataplerosis of the TCA cycle and increasing the availability of AcCoA for oxidation by decreasing its export from the liver as ketone bodies. Insulin also stimulates lipogenesis and suppresses lipolysis (Brockman and Laarveld, Reference Brockman and Laarveld1986), reducing the concentration of NEFA in the blood. Non-esterified fatty acids are the primary source of AcCoA and are extracted from the blood in proportion to their concentrations (Bell, Reference Bell1980). Plasma concentrations of insulin and NEFA are inversely related over the long term as well as within the timeframe of meals with pulsatile insulin release in response to absorbed fuels (Allen, Reference Allen2014). Insulin also stimulates the uptake of AA by muscle tissue and inhibits protein degradation (Brockman and Laarveld, Reference Brockman and Laarveld1986; Lobley, Reference Lobley1992). The mobilization of AA from the muscle occurs during negative energy balance when plasma insulin concentration is low (Heitmann and Bergman, Reference Heitmann and Bergman1980). Amino acids can be oxidized in the TCA cycle after conversion to AcCoA, and glucogenic AA are anaplerotic and can stimulate the oxidation of AcCoA.

Glucagon has both direct and indirect effects on plasma NEFA concentrations (Bobe et al., Reference Bobe, Sonon, Ametaj, Young and Beitz2003) by directly increasing lipolysis (Brockman, Reference Brockman1976) but indirectly decreasing lipolysis by increasing the concentrations of glucose and insulin (Brockman, Reference Brockman1978). Therefore, the net effect on lipolysis and NEFA supply to the liver is dependent upon responses of glucose and insulin (Bobe et al., Reference Bobe, Sonon, Ametaj, Young and Beitz2003). Glucagon stimulates gluconeogenesis in bovine hepatocytes in vitro, but the response is counteracted by insulin (Donkin and Armentano, Reference Donkin and Armentano1995). Chronic elevation of plasma insulin concentrations inhibits gluconeogenesis, decreasing cataplerosis of TCA intermediates and likely stimulating hepatic oxidation within meals sooner (Allen, Reference Allen2014).

Somatotropin has a range of biological effects, including stimulation of milk synthesis, increased AA and glucose uptake by the muscle and mammary gland, increased protein synthesis and accretion by skeletal muscle, increased glucose output by the liver and decreased ability of insulin to inhibit gluconeogenesis, increased basal lipolysis during negative energy balance and decreased lipid synthesis during positive energy balance (Etherton and Bauman, Reference Etherton and Bauman1998). Although somatotropin secretion is pulsatile with irregular pulses in cattle (Kayusa, Reference Kayusa2016), its effects on lipolysis are chronic with no acute effects in ruminants (Houseknecht et al., Reference Houseknecht, Bauman, Vernon, Byatt and Collier1996). Somatotropin likely stimulates feed intake by hepatic oxidation by reducing TCA intermediates; cataplerosis is increased by increasing gluconeogenesis, and anaplerosis is decreased by reducing AA supply to the liver.

Leptin has been implicated in the control of feed intake, and plasma leptin concentration is correlated with body fat percent and body condition score in lactating cows (Ehrhardt et al., Reference Ehrhardt, Slepetis, VanAmburgh, Siegal-Willot, Bell and Boisclair2000). Leptin treatment of animals causes a dose-dependent decrease in feed intake, and a loss of body weight and fat depots (Pelleymounter et al., Reference Pelleymounter, Cullen, Baker, Hecht, Winters, Boone and Collins1995). The role of leptin on the regulation of body weight balance is consistent with a fat-related lipostatic signal to the brain, proposed by Kennedy (Reference Kennedy1953). Leptin increases lipolysis and plasma NEFA concentrations by inhibiting insulin release by the pancreas (Emilsson et al., Reference Emilsson, Liu, Cawthorne, Morton and Davenport1997; Kieffer et al., Reference Kieffer, Heller, Leech, Holz and Habener1997) and suppressing lipogenesis and increasing triglyceride hydrolysis (Houseknecht et al., Reference Houseknecht, Baile, Matteri and Spurlock1998; Harris, Reference Harris2014). Whereas leptin’s effects on food intake are thought to be mediated centrally via neurotransmitters (Houseknecht et al., Reference Houseknecht, Baile, Matteri and Spurlock1998), its effects on feed intake might also be from increasing the supply of AcCoA for hepatic oxidation by elevating plasma NEFA concentrations (Allen, Reference Allen2014).

Insulin resistance is attributed to decreased maximal effect of insulin (insulin responsiveness) and decreased insulin sensitivity (the concentration of insulin to elicit a half-maximal response; Kahn, Reference Kahn1978). The effects of insulin on stimulating lipogenesis and inhibiting lipolysis in adipose tissue are affected by various factors (Vernon, Reference Vernon1980). Insulin resistance varies among animals and physiological states, modulating the effects of insulin on plasma NEFA concentrations and its supply to the liver. Hyperinsulinemia can cause insulin resistance by downregulating insulin receptors and desensitizing post-receptor pathways (Kahn and Flier, Reference Kahn and Flier2000). Insulin resistance of adipose tissue has been positively related to somatotropin in dairy cows (Boisclair et al., Reference Boisclair, Bauman, Bell, Dunshea and Harkins1994; Bell and Bauman, Reference Bell and Bauman1997), and a long-term administration of the pro-inflammatory adipokine TNF-α induced insulin resistance in steers (Kushibiki et al., Reference Kushibiki, Hodate, Shingu, Ueda, Mori, Itoh and Yokomizo2001). In contrast, the anti-inflammatory adipokine adiponectin was negatively related to insulin resistance in cows (Giesy et al., Reference Giesy, Yoon, Currie, Kim and Boisclair2012).

Metabolites affect insulin sensitivity directly by modulating the insulin-signaling pathway, and alter the protein function by post-translational modification by metabolites (e.g. acetylation and palmitoylation; Yang et al., Reference Yang, Vijayakumar and Kahn2018). Sustained elevation of plasma NEFA can interfere with insulin signaling, increasing insulin resistance (Le Marchand-Brustel et al., Reference Le Marchand-Brustel, Gual, Grémeaux, Gonzalez, Barrès and Tanti2003). Hyperlipidemia impairs the ability of insulin to suppress gluconeogenesis, stimulates glucose uptake into skeletal muscle and inhibits insulin secretion from the pancreas (Kahn and Flier, Reference Kahn and Flier2000). However, NEFA differ in their effects on insulin sensitivity. Saturated FA impair insulin signaling and decrease insulin sensitivity, whereas some unsaturated FA, including the polyunsaturated eicosapentaenoic and docosahexaenoic acids and monounsaturated oleic and palmitoleic acids, are associated with improved insulin sensitivity (Yang et al., Reference Yang, Vijayakumar and Kahn2018). β-hydroxybutyrate inhibits lipolysis in adipose tissue (Taggart et al., Reference Taggart, Kero, Gan, Cai, Cheng, Ippolito, Ren, Kaplan, Wu, Wu, Jin, Liaw, Chen, Richman, Connolly, Offermanns, Wright and Waters2005), providing negative feedback when AcCoA is in excess.

Interactions of diet and physiological state

The physiological state varies greatly across the lactation cycle, including the prepartum period when preparing for the transition from pregnancy to lactation; the immediate postpartum period characterized by a lipolytic state; peak lactation when cows are in negative energy balance and feed intake is increasingly limited by distention; and mid- to late lactation when milk yield decreases and body energy stores replete (Table 1). The effects of diet composition on feed intake are affected by the physiological state of animals (Allen and Piantoni, Reference Allen and Piantoni2014), and the interactions of diet and physiological state are related to the supply of AcCoA, and the balance between anaplerosis and cataplerosis of the TCA cycle (Figure 2).

Table 1

Relative status of characteristics related to the control of feed intake at different stages of lactation in cattle

L = low level; M = medium level; H = high level.

Figure 2

Effects of diet and physiological state on hepatic concentrations of acetyl CoA (AcCoA) and the tricarboxylic acid (TCA) cycle intermediates in ruminant animals. (1) The primary source of AcCoA is β-oxidation of non-esterified fatty acids (NEFA) extracted from the blood. (2) Other sources of AcCoA include amino acids (AA), lactate, glycerol, butyrate and medium-chain FA. (3) AcCoA enters the TCA cycle for oxidation combining with oxaloacetate (OAA) to form citrate. Acetyl CoA is also (4) used in biosynthetic reactions, (5) exported as ketone bodies and (6) hydrolyzed to acetate and released into the bloodstream. The oxidation of AcCoA in the TCA cycle is dependent upon the supply of OAA produced from TCA intermediates. The concentration of TCA intermediates is determined by the balance between anaplerosis and cataplerosis. (7) Anaplerotic metabolites include those of dietary origin, including propionate, glucogenic AA, lactate and glycerol, as well as endogenous sources including lactate, glucogenic AA and glycerol. The rate of anaplerosis by metabolites of dietary origin is highly variable depending upon the diet and the kinetics of digestion and passage. Propionate entry is pulsatile post-prandially as it can be produced, absorbed and extracted from the blood very quickly within the time-course of meals. Other anaplerotic metabolites derived from the diet (e.g. glucogenic AA, lactate) are absorbed post-ruminally with a greater latency for absorption and likely contribute to anaplerosis between meals. (8) Cataplerosis decreases the concentration of TCA intermediates, which are used for gluconeogenesis and other biosynthetic reactions.

Anaplerosis v. cataplerosis: stimulation of acetyl CoA oxidation

Intermediates of the TCA cycle that provide OAA for the citrate synthase reaction and used for gluconeogenesis and other biosynthetic reactions are replenished by anaplerotic metabolites derived from the diet and tissues. Propionate is the primary anaplerotic metabolite stimulating hepatic oxidation within the timeframe of meals (Allen, Reference Allen2000). Propionic acid is produced primarily by the fermentation of starch by rumen microbes and can be produced and absorbed as propionate at very high rates and efficiently extracted by the liver within the timeframe of meals (Allen, Reference Allen2000). Other anaplerotic metabolites derived from the diet (e.g. glucogenic AA, lactate) are absorbed post-ruminally with a greater latency for absorption and likely contribute to hepatic oxidation extending satiety post-prandially (Allen et al., Reference Allen, Bradford and Oba2009). Although glycerol and propionate are both 3-carbon glucose precursors with similar energy concentrations, they have different hypophagic effects because propionate is an obligate anaplerotic metabolite, whereas glycerol can enter the gluconeogenic pathway as glyceraldehyde-3-phosphate in the cytosol without stimulating hepatic oxidation. Consistent with this, propionic acid decreased DMI 17% relative to glycerol by decreasing meal size when isoenergetic solutions were infused abomasally in cows in the postpartum period (Gualdrón-Duarte and Allen, Reference Gualdrón-Duarte and Allen2017).

The production rate of propionic acid by rumen microbes is highly variable depending upon source (Allen, Reference Allen2000). The starch concentration of diets consumed by ruminants is highly variable ranging from <5% for some grazing ruminants to >30% for some lactating dairy cows and fattening steers. Starch degradation by rumen microbes varies from <50% to >90% (Nocek and Tamminga, Reference Nocek and Tamminga1991). Starch that passes from the rumen can be digested to glucose in the intestine, which is absorbed and enters the circulation or is metabolized to lactate by intestinal tissues. Although increasing dietary starch can increase feed intake when cereal grains are substituted for forages by decreasing ruminal distention (Allen, Reference Allen1996), increased ruminal starch fermentability decreased feed intake by up to 3 kg/day in several experiments reported in the literature (Allen, Reference Allen2000). High-moisture corn decreased energy intake of cows in the postpartum period to a greater extent when fed in rations at higher starch concentrations (28% v. 22%) compared with less fermentable dry ground corn (Albornoz and Allen, Reference Albornoz and Allen2018). Hypophagic effects of a more fermentable starch source in lactating cows were from decreased meal size despite a decreased inter-meal interval, so satiety was likely caused by the absorption of propionate within the timeframe of meals (Oba and Allen, Reference Oba and Allen2003b).

Of the fuels available from the fermentation and digestion of starch, propionate is the most hypophagic. Intraruminal infusion of propionate decreased metabolizable energy intake compared with acetate (Oba and Allen, Reference Oba and Allen2003c), and propionic acid decreased metabolizable energy intake compared with isoenergetic infusion of glucose and reduced DMI compared with isoenergetic infusions of lactic acid when infused into the abomasum (Gualdrón-Duarte and Allen, Reference Gualdrón-Duarte and Allen2018). Intraruminal infusion of propionic acid reduced metabolizable energy intake by cows in the postpartum period compared with cows in mid-lactation (Oba and Allen, Reference Oba and Allen2003a). Although gluconeogenesis is upregulated for cows in the postpartum period, they were in a lipolytic state with elevated plasma BHB concentrations, whereas cows in mid-lactation were in positive energy balance with low plasma concentrations of BHB. Differences in plasma BHB concentrations likely reflect differences in the supply of AcCoA for hepatic oxidation, consistent with the greater hypophagic effects of propionic acid for cows in the postpartum period. In addition, the hypophagic effects of intraruminal infusions of propionic acid were related linearly with hepatic AcCoA concentrations for cows in the postpartum period (Stocks and Allen, Reference Stocks and Allen2012), and the effects were not attenuated over a 3-day intraruminal infusion (Stocks and Allen, Reference Stocks and Allen2013). It is noteworthy that propionate interacted with AcCoA in the liver to affect feed intake only during the first 4 h after feeding each day; daily DMI was reduced despite no effect of treatment on feed intake over the remaining 20 h (Stocks and Allen, Reference Stocks and Allen2013). This is likely because plasma NEFA concentrations are greatest prior to feeding and lowest several hours after feeding corresponding to the daily peak in plasma insulin concentrations for cows fed ad libitum once per day in the morning (Allen et al., Reference Allen, Bradford and Harvatine2005).

Chronic elevation of plasma insulin concentrations likely suppresses feed intake by decreasing cataplerosis, but pulsatile insulin secretion in response to feeding likely clears fuels from the blood more quickly, potentially increasing meal size or decreasing the interval between meals (Oba and Allen, Reference Oba and Allen2000). Concentrations of insulin and NEFA in plasma vary within days and are negatively related on a minute timescale (Figure 3). The depression in feed intake of lactating cows to a more fermentable diet was correlated positively to the insulin response to a glucose challenge; cows with a greater insulin response were better able to maintain feed intake on the more fermentable diet (Bradford and Allen, Reference Bradford and Allen2007). Postprandial pulses of insulin interrupt the supply of fuels to the liver by stimulating the uptake of fuels by insulin-sensitive tissues and inhibiting lipolysis in adipose issue. Consistent with this, feed intake over the first 4 h following feeding was highly variable among cows in the immediate postpartum period ranging from 3.7 to 9.6 kg and was positively related to the postprandial reduction of plasma NEFA concentrations which varied from 244 to 1158 µEq/l (Piantoni et al., Reference Piantoni, Ylioja and Allen2015). Because the change in hepatic AcCoA concentrations was positively correlated with the change in plasma NEFA concentrations, the difference in DMI among cows was likely related to differences in the supply of AcCoA derived from β-oxidation of NEFA, consistent with the HOT. Furthermore, because DMI was not related with plasma concentrations of glucose, insulin, NEFA and BHB, or hepatic concentrations of AcCoA before feeding, or to the change in plasma glucose, insulin or BHB over the 4-h period, the variation in DMI was likely because of differences in insulin resistance among cows.

Figure 3

Inverse relationship between plasma insulin (grey line) and non-esterified fatty acid (NEFA; black line) concentrations for an individual cow within a day. Cow was fed ad libitum, once per day with blood samples taken every 20 min for 24 h. Increased insulin during and following meals decreases the supply of NEFA for hepatic oxidation, while decreased insulin gradually increases NEFA supply following meals (Allen, Reference Allen2014 with permission).

The mobilization of tissue AA begins prepartum (Doepel et al., Reference Doepel, Lapierre and Kennelly2002; Kokkonen et al., Reference Kokkonen, Taponen, Anttila, Syrjala-Qvist, Delavaud, Chilliard, Tuori and Tesfa2005), and high-yielding dairy cows might mobilize up to 1 kg of tissue protein per day in the early postpartum period (Bell et al., Reference Bell, Burhans and Overton2000). Although AA are used for milk protein synthesis in the postpartum period (Aschenbach et al., Reference Aschenbach, Kristensen, Donkin, Hammon and Penner2010), excess AA and AA imbalances will result in deamination of AA, increasing anaplerosis and stimulating the oxidation of AcCoA, potentially suppressing feed intake (Allen, Reference Allen2014). A meta-analysis by Martineau et al. (Reference Martineau, Ouellet, Kebreab and Lapierre2016) showed that DMI of cows ranging from early to late lactation was reduced by abomasal infusion of casein when supply of metabolizable protein (MP) was positive but increased DMI of cows when MP balance was negative. When MP supply was positive, excess AA were likely deaminated, increasing anaplerosis and stimulating hepatic oxidation and satiety, whereas increased DMI by casein infusion when MP supply was negative might have been because of increased metabolic pull. Supplementation of rumen-protected methionine has had variable effects on DMI (Patton, Reference Patton2010; Zanton et al., Reference Zanton, Bowman, Vázquez-Añón and Rode2014), and Allen (Reference Allen2014) suggested that supplying limiting AA will likely decrease deamination of other AA and anaplerosis, potentially increasing DMI.

Gluconeogenesis is likely an important determinant of the temporal oxidation of fuels in the liver by increasing cataplerosis of the TCA cycle. The contribution of substrates to gluconeogenesis has been estimated to be propionate (60% to 75%), lactate (16% to 26%), alanine (5%) and other AA (8% to 11%), valerate and isobutyrate (5% to 6%) and glycerol (0.5% to 3%; Aschenbach et al., Reference Aschenbach, Kristensen, Donkin, Hammon and Penner2010). In the immediate postpartum period, the contribution of propionate to gluconeogenesis (∼60%) is less, and mostly endogenous lactate (∼26%) is greater than several weeks later in lactation; together, they account for over 85% of gluconeogenic substrates extracted from the blood by the liver (Aschenbach et al., Reference Aschenbach, Kristensen, Donkin, Hammon and Penner2010). Gluconeogenesis is upregulated in early lactation when plasma insulin concentration is low and gradually downregulated by elevated insulin concentrations (Barthel and Schmoll, Reference Barthel and Schmoll2003) as lactation advances and glucose demand decreases. However, excessive lipolysis in the peripartum period can result in hepatic steatosis, reducing gluconeogenesis (Zhu et al., Reference Zhu, Armentano, Bremmer, Grummer and Bertics2000). The depression of DMI by a diet containing a more rapidly fermentable starch source was correlated positively (r = 0.53, P < 0.01) with plasma insulin concentrations among cows past peak lactation, likely because gluconeogenesis was suppressed by insulin (Bradford and Allen, Reference Bradford and Allen2007). The downregulation of gluconeogenesis decreases cataplerosis, increasing the concentrations of TCA intermediates and TCA cycle capacity for oxidation.

More questions

Questions remain regarding the mechanism(s) by which oxidation of fuels by hepatocytes is conveyed to hepatic vagal afferent nerves as well as how hepatic oxidation can be manipulated to alter (increase or decrease) feed intake. Feeding behavior is controlled on a minute-to-minute basis, but little research has evaluated hepatic metabolism over the timeframe of meals. Comprehensive evaluation of metabolite concentrations and isotopic tracer studies are needed to better understand hepatic metabolism over the short term related to feeding behavior. Genetic differences in feed intake among animals have yet to be investigated for factors related to hepatic oxidation of fuels. Differences in the rate of uptake of NEFA from the blood by the liver, peroxisomal oxidation of FA, transport of FA into the mitochondria, rate of production and export of ketone bodies, and rate of hydrolysis of AcCoA and export of acetate from the liver might affect feed intake by their effects on hepatic oxidation. In addition, differences among animals or physiological states for insulin release or insulin sensitivity of adipose tissue might decrease lipolysis within meals, decreasing the supply of AcCoA for oxidation, increasing meal length and size.