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© 2007 The American Society for Nutrition J. Nutr. 137:326-330, February 2007

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Phlorizin Administration Does Not Attenuate Hypophagia Induced by Intraruminal Propionate Infusion in Lactating Dairy Cattle1

Barry J. Bradford2 and Michael S. Allen*

Department of Animal Science, Michigan State University, East Lansing, MI 48824

* To whom correspondence should be addressed. E-mail: allenm{at}msu.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 LITERATURE CITED
 
Infusion data from ruminants has shown that propionate stimulates satiety and decreases meal size, possibly because of increased propionate oxidation in the liver. In this experiment, phlorizin was used to increase glucose demand, which was expected to decrease propionate oxidation and attenuate the decrease in dry matter intake (DMI) caused by propionate infusion. Twelve multiparous, ruminally-cannulated Holstein cows (49 ± 33 d in milk, 40 ± 7 kg/d milk; mean ± SD) were randomly assigned to square and treatment sequence in a replicated 4 x 4 Latin square experiment with a 2 x 2 factorial arrangement of treatments. Treatments were subcutaneous injection of phlorizin or propylene glycol in combination with intraruminal infusion of either Na acetate or Na propionate. Following a 7-d adaptation period, phlorizin (4 g/d) and control injections were administered every 6 h for 7 d. During the final 2 d of injections, Na acetate or Na propionate solutions (1 mol/L, pH 6.0) were infused continuously at the rate of 0.80 L/h. Feeding behavior data were collected during the final 2 d of treatment. Phlorizin caused urinary excretion of 400 ± 40 g glucose/d across infusion treatments. Phlorizin tended to increase plasma free fatty acid and ß-hydroxybutyrate concentrations to a greater extent with Na acetate compared to Na propionate infusion (both interactions P < 0.15). Phlorizin decreased and Na propionate increased plasma insulin and glucose concentrations. Infusion of Na propionate decreased DMI (18.4 vs. 21.1 ± 1.4 kg/d, P < 0.001) through an increase in intermeal interval (89.2 vs. 77.3 ± 6.6 min, P = 0.03), resulting in fewer meals per day (11.6 vs. 13.7 ± 0.7, P < 0.001). Phlorizin did not alter DMI (P = 0.39) or measures of feeding behavior, nor were there interactions with infusion type. Increasing glucose demand does not limit the extent to which propionate decreases DMI in lactating dairy cows.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 LITERATURE CITED
 
Propionate, a product of ruminal carbohydrate metabolism, depresses feed intake of ruminants. Although the mechanism for this hypophagic response is unknown, a strong body of evidence indicates that the liver is involved. Propionate infusion depresses feed intake to a greater extent when infused into the portal circulation compared to peripheral infusion (1,2) and blocking autonomic nervous system pathways between the brain and liver eliminated hypophagic responses to propionate infusion (2,3). Forbes (4) has pointed out that propionate and many other substrates oxidized by the liver have demonstrable effects on food intake, whereas the products of these oxidation reactions do not. Increased feed intake was induced in nonruminants by blocking hepatic oxidation of fatty acids (5,6) and by preventing ATP production through phosphate trapping (7), providing more direct evidence for the involvement of hepatic oxidation in feed intake regulation.

Evidence regarding the feed intake effects of hepatic oxidation by ruminant liver is currently lacking. Although at least some propionate is oxidized by ruminant liver (8), the majority of propionate entering the liver is utilized for gluconeogenesis. Propionate infusion alters feed intake primarily through decreased meal size (9) and we hypothesized that the increased flux of propionate into the liver during meals (10) results in excess glucogenic substrate availability and greater oxidation of propionate, stimulating satiety. To test this hypothesis, we used phlorizin to cause urinary loss of glucose; we previously provided evidence of an adaptive increase in gluconeogenic capacity in response to phlorizin administration in lactating cows (11). We expected phlorizin to direct more propionate toward glucose production and to limit the hypophagic response to propionate infusion.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 LITERATURE CITED
 
Experimental procedures were approved by the All-University Committee on Animal Use and Care at Michigan State University.

    Design and treatments. Twelve multiparous lactating Holstein cows (49 ± 33 d in milk, 40 ± 7 kg/d milk; mean ± SD) with ruminal cannulas were selected from the Michigan State University Dairy Cattle Teaching and Research Center and randomly assigned to square and treatment sequence in a replicated 4 x 4 Latin square design balanced for carry-over effects. A 2 x 2 factorial arrangement of treatments was used to assess effects of phlorizin in combination with infusion of Na acetate or Na propionate. During treatment periods, phlorizin (Sigma Chemical) was administered via subcutaneous injection every 6 h at the rate of 4 g/d, with propylene glycol as vehicle and control. Treatment periods were 7 d, sufficient to allow for metabolic and transcriptional adaptations to phlorizin (11). During the final 2 d of phlorizin treatment, solutions of Na acetate or Na propionate (1.0 mol/L, pH 6.0) were continuously infused into the rumen at the rate of 0.80 ± 0.07 L/h. The iso-osmotic acetate solution was chosen as an infusion control because it is the most abundant SCFA produced in the rumen and it allows us to rule out potential osmotic effects of propionate infusion. Although acetate and propionate treatments were not isoenergetic, propionate infusion has been shown to decrease energy intake (including energy from infusates and feed consumed) of lactating cows after as little as 12 h of treatment (12). Solutions were infused using 4-channel peristaltic pumps (no. 78016–30, Cole-Parmer Instrument) and Tygon tubing (7.5 m x 1.6-mm i.d.; Fisher Scientific). The cows were adapted to a single diet for a 7-d period before the first treatment period, and 7 d of rest were included between treatment periods. Throughout the experiment, cows were housed indoors in tie stalls and fed a total mixed ration once daily (1130 h) at 110% of that animal's typical daily intake. The diet (455 g dry matter/kg diet, Table 1) was formulated to meet nutrient requirements (13) and to promote endogenous propionate production. One cow was removed from treatment in period 1 for clinical ketosis and a second cow was removed from the experiment in period 4 for mastitis, leaving 11 observations for each of the acetate treatments.


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  		TABLE 1 Ingredients and nutrient composition of experimental diet

 
    Data and sample collection. Access to feed was prevented for 90 min each day (1000 to 1130 h) while orts and the amount of feed offered were weighed for each cow. During the final 2 d of each treatment period, feeding behavior was monitored by a computerized data acquisition system (14) throughout the day. Data on feed disappearance and water consumption were recorded for each cow every 5 s, and mean daily values for number of meal bouts, interval between meals, and meal size were calculated. On each data collection day, samples of all dietary ingredients (0.5 kg) and orts (12.5%) were collected. Cows were milked in tie stalls during data collection and in the milking parlor during the rest of the experiment. Milk yield was recorded and samples were taken at each milking during collection days.

Urine was collected for a 24-h period on day 7 (1100 h) of each treatment period. Urinary catheters (Bardex Lubricath Foley 24FR, Bard Medical) were inserted and urine was collected in a container with 38 mL of 6 mol/L HCl added to prevent glycolysis. Volumes were measured at 6-h intervals and samples were taken and frozen until analysis. During the same 24-h period, blood samples were collected at 3-h intervals from indwelling jugular catheters. Collected blood was processed and stored as described (11). At the end of each data collection period, we sampled ruminal contents from 5 sites throughout rumen and squeezed them through a nylon screen (1-mm pore size) to collect the liquid phase. Ruminal fluid pH was measured using a portable pH meter (model 230A, ATI Orion) and samples were frozen at –20°C until analysis.

    Sample analysis. Diet ingredients, orts, and fecal samples were dried in a 55°C forced-air oven for 72 h and analyzed for dry matter concentration. We ground ingredient samples with a Wiley mill (1-mm screen; Authur H. Thomas) and analyzed them for ash, neutral detergent fiber, crude protein, and starch content as previously described (11). Concentrations of all nutrients are expressed as percentages of dry matter determined from drying at 105°C in a forced-air oven. We analyzed milk samples for fat, true protein, and lactose with infrared spectroscopy by the Michigan Dairy Herd Improvement Association. In addition, milk samples from d 7 of each treatment period were analyzed for fatty acid profile by GC as previously described (15). Urine and plasma samples were analyzed in duplicate for glucose content by the glucose oxidase method (16). Plasma samples were analyzed using commercial kits to determine concentrations of FFA, ß-hydroxybutyrate (BHBA),3 insulin, and glucagon as previously described (11). Concentrations of SCFA in ruminal fluid were determined as previously described (17).

    Statistical analysis. Data were analyzed by the fit model procedure of JMP (version 5.0, SAS Institute) using the REML method according to the following model:

Formula

where Yijkl is a dependent variable, µ is the overall mean, Pi is the fixed effect of period (i = 1–4), Sj is the fixed effect of square (j = 1–3), Ck is the random effect of cow within square (k = 1–4), Tl is the fixed effect of treatment (l = 1–4), PTil is the interaction of period and treatment, V is the effect of infusion volume, VTl is the interaction of infusion volume and treatment, and eijk is the residual error. Infusion volume was included in the model to account for potential bias caused by variation in infusion rate across cows and periods. Period by treatment interactions were not significant for any variable except milk lactose yield; modeling potential carryover effects for this variable did not resolve the issue, so treatment effects could not be assessed. Plasma data were analyzed by a model including the above terms as well as the effects of sample time and time by treatment interaction; repeated measures over time were modeled with a heterogeneous autoregressive [ARH(1)] covariance structure using the repeated statement of SAS (version 9.0, SAS Institute) and denominator degrees of freedom were estimated using the Kenward Rogers method. For all main effects, significance was declared at P < 0.05 and tendencies were declared at P < 0.10. Interactions were declared significant at P < 0.10 and tendencies for interactions were declared at P < 0.15.


   Results and Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
LITERATURE CITED
 
Phlorizin administration caused urinary loss of glucose at the rate of 400 g/d across infusion treatments (Table 2), consistent with previous results in lactating cows (11,18). Also as expected, infusion of acetate or propionate increased ruminal concentrations of the respective SCFA (P < 0.001). More surprisingly, phlorizin treatment tended to decrease ruminal propionate concentration (P < 0.10) and propionate infusion decreased ruminal butyrate concentration relative to acetate infusion (P < 0.01). Plasma glucose concentration was altered both by substrate availability and by peripheral demand; glucose concentrations increased in response to propionate infusion (P < 0.001) and decreased with phlorizin treatment (P < 0.01). Changes in plasma insulin and glucagon concentrations were expected responses to treatment effects on plasma glucose concentration (Table 2).


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  		TABLE 2 Effects of phlorizin and SCFA infusion on glucose excretion, ruminal SCFA, and blood plasma metabolites and hormones1

 
In past experiments, we have consistently found that both increased dietary starch fermentability and propionate infusion depress feed intake primarily through decreased meal size (9,12,17). However, in this experiment, propionate infusion increased intermeal interval (P = 0.04, Table 3) with no effect on meal size. Management, ration formulation, and infusion protocols were similar in this experiment compared to our past work, making it difficult to determine why the feeding behavior response was different in this case. Past work has indicated that mid-lactation cows (similar to those used in this experiment) consistently increased intermeal interval in response to propionate infusion, whereas that was not the case for early lactation cows (9); perhaps metabolic effects on feed intake are mediated primarily through meal frequency in cows nearing peak lactation.


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  		TABLE 3 Effects of phlorizin and SCFA infusion on feeding behavior and yield of milk components1

 
In previous experiments with lactating ruminants, phlorizin induced a catabolic state resulting in increased availability of FFA at the liver (11,18–20). Phlorizin caused increases of similar magnitude in plasma FFA and BHBA concentrations with acetate infusion in this experiment (Table 2). However, propionate infusion significantly decreased FFA and BHBA concentrations; furthermore, tendencies for treatment interactions for both FFA and BHBA suggest that marginal responses to phlorizin were decreased by propionate infusion (Table 2). Plasma FFA analyses provide a reasonable assessment of fatty acid mobilization in ruminants (21). On the other hand, plasma glycerol is indicative of lipolysis, and phlorizin increased plasma glycerol concentrations across infusion treatments (P = 0.02, Table 2). Analysis of milk components offers the advantage of providing a composite view of nutrient availability over the course of the day. De novo lipogenesis in the ruminant mammary gland produces fatty acids with chain lengths up to 16 carbons, but long-chain fatty acids (LCFA) exceeding 16 carbons are plasma derived (22). Because phlorizin treatment had no influence on dietary lipid intake, any treatment effects on LCFA can be attributed to differences in lipolytic activity. Although there was no significant effect of phlorizin on LCFA yield (P = 0.29, Table 3), numerical increases in LCFA yield accounted for 32% and 88%, respectively, of the significant increase in milk fat yield for phlorizin treatment with acetate and propionate infusions. No other class of fatty acids could account for the increase in milk fat yield with phlorizin. Taking into account treatment effects on plasma FFA, plasma glycerol, and milk fat yield, it seems likely that lipolysis, and delivery of fatty acids to the liver, was increased by phlorizin across infusion treatments.

As expected, propionate infusion decreased dry matter intake (DMI) relative to acetate infusion (18.7 vs. 21.5 kg/d, P < 0.001, Table 3); according to our working hypothesis, this was because propionate infusion stimulated hepatic oxidation of propionate (23). Phlorizin is expected to increase utilization of propionate for gluconeogenesis (24) and we predicted that this would limit the hypophagic effects of propionate infusion. However, we found no overall effect of phlorizin on DMI (P = 0.39, Table 3), nor was an interaction with infusion treatment evident (P = 0.91). These data do not support our hypothesis; however, treatment effects on fatty acid availability for hepatic oxidation confound the targeted effects on propionate and glucose metabolism.

A number of alternative hypotheses have been suggested to explain the hypophagic effects of propionate in ruminants. Propionate is an insulin secretagogue, and both propionate infusions and rations with large amounts of highly digestible starch typically increase plasma insulin concentrations (25). Insulin is a potent satiety factor when administered via intracerebroventricular infusion in sheep (26) and it can access the central nervous system through the blood-brain barrier (27). However, propionate infusions have decreased DMI without increasing plasma insulin concentrations (28), and in one study, propionate infusion failed to decrease DMI despite nearly tripling jugular insulin concentrations (29). Within propionate infusions in this experiment, phlorizin treatment tended to decrease insulin concentration (68 vs. 79 pmol/L, P = 0.06) while numerically decreasing DMI; at least in this case, insulin did not mediate propionate's hypophagic effects.

Nutrient receptors in the veins draining the splanchnic bed have been proposed for propionate in ruminants (1,29) and glucose in nonruminants (30). Glucose is hypophagic in a variety of nonruminants (31), but intestinal and intravenous glucose infusions did not decreased energy intake of ruminants (32). The absence of effects of portal glucose infusion on feed intake by sheep (33) casts doubt on the hypothesis that sensory neurons in the portal vein mediate the hypophagic effects of glucose, given that mechanisms regulating feed intake are well conserved across divergent species (34). There is broad consensus now that portal glucose infusions modulate feed intake of nonruminants through oxidation of glucose (35), but there is disagreement as to whether this occurs in sensory neurons or hepatocytes. Because ruminant neural tissue metabolizes glucose (36), it seems unlikely that hypophagia is induced by glucose oxidation in sensory receptors. Rather, differences in hypophagic effects of glucose infusion observed between ruminants and nonruminants are likely because of differences in hepatic oxidation of glucose; liver hexokinase activity is low in ruminants compared with nonruminants (37), and in mature ruminants, hepatic removal of glucose appears to be negligible (38). Likewise, the responses attributed to the proposed propionate receptor can be explained equally well by the hepatic oxidation hypothesis without the need to propose dramatic evolutionary divergence in mechanisms regulating feed intake.

Evidence regarding the mechanism for propionate's hypophagic effects in ruminants remains elusive. These data and other recent findings suggest that short-term (7 d) increases in glucose demand do not alter feed intake response to propionate infusion or highly fermentable diets (11). Adaptive physiological responses such as increased lipolysis and protein breakdown may provide oxidative fuel and glucogenic substrate for enhanced gluconeogenesis during phlorizin administration, preventing the increase in feed intake that was expected in response to urinary loss of ~5% of net energy intake.


   ACKNOWLEDGMENTS
 
The authors thank R. E. Kreft, R. A. Longuski, D. G. Main, Y. Ying, and J. A. Voelker Linton for their technical assistance.


   FOOTNOTES
 
1 Supported by the National Research Initiative Competitive Grant no. 2004-35206-14167 from the USDA Cooperative State Research, Education, and Extension Service and a National Science Foundation Graduate Research Fellowship. Back

2 Present address: 127 Call Hall, Kansas State University, Manhattan, KS 66506. Back

3 Abbreviations used: BHBA, ß-hydroxybutyrate; DMI, dry matter intake; LCFA, long-chain fatty acid. Back

Manuscript received 29 September 2006. Initial review completed 6 November 2006. Revision accepted 13 November 2006.


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 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 LITERATURE CITED
 

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