Source: MICHIGAN STATE UNIV submitted to
PROPIONATE REGULATION OF FEED INTAKE
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
TERMINATED
Funding Source
Reporting Frequency
Annual
Accession No.
0198478
Grant No.
2004-35206-14167
Project No.
MICL08320
Proposal No.
2003-03298
Multistate No.
(N/A)
Program Code
42.0
Project Start Date
Dec 1, 2003
Project End Date
Nov 30, 2006
Grant Year
2004
Project Director
Allen, M. S.
Recipient Organization
MICHIGAN STATE UNIV
(N/A)
EAST LANSING,MI 48824
Performing Department
ANIMAL SCIENCE
Non Technical Summary
Energy intake is a primary limitation on milk yield, reproduction, and health for genetically superior dairy cows. Propionate is a major inhibitory regulator of feed intake by dairy cows, but the mechanism is not understood. This proposal focuses on regulation of feed intake by propionate. Infused propionate has been widely reported to depress feed intake in ruminants. Absorbed propionate is nearly completely cleared by the liver where it is converted to glucose or oxidized. Oxidation of fuels in the liver has been reported to depress feed intake for non-ruminant species. Of fuels metabolized by the ruminant liver, propionate is likely a primary satiety signal because its flux to the liver increases greatly during meals. Our overall hypothesis is that feed intake is regulated by propionate oxidation in the liver. We will determine metabolic and feeding behavior responses of lactating cows to increased glucose demand, determine interactions for metabolic and feeding behavior responses between glucose demand and propionate supply and determine if feed intake response by individual cows to increased propionate supply from a more fermentable diet is related to gluconeogenic capacity. We expect to find evidence consistent with our hypothesis that the ability of propionate to depress feed intake is related to its oxidation in the liver. Elucidation of the basic mechanisms for regulation of feed intake by propionate will provide the foundation for development of novel nutritional or pharmacological approaches to increase energy intake and milk yield of dairy cows.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
30234101010100%
Goals / Objectives
Determine metabolic and feeding behavior responses of lactating cows to increased glucose demand. Determine interactions for metabolic and feeding behavior responses between glucose demand and propionate supply. Determine if feed intake response by individual cows to increased propionate supply from a more fermentable diet is related to gluneogenic capacity.
Project Methods
We will increase glucose demand of lactating cows by administering phlorizin, a compound that inhibits renal glucose reabsorption, and expect cows to increase feed intake because of increased meal size. We further expect mRNA concentrations for gluconeogenic enzymes in the liver, regulated by gene expression or RNA stability, to increase with glucose demand. We will infuse propionate and acetate intraruminally and expect that the hypophagic effects of propionate compared to acetate will be reduced by increased glucose demand by administering phlorizin. We will evaluate relationships between feed intake response of cows to increased diet fermentability and milk yield, plasma glucose concentration, and measures of gluconeogenic capacity, such as rate of propionate conversion to glucose and mRNA concentrations for gluconeogenic enzymes. A functional genomics approach will be used to compare cows with the greatest depression and least depression in DMI to a more fermentable diet. We expect to find differences in genes that are related to the fate of propionate in the liver that will lead to further research to help us discover mechanisms regulating feed intake.

Progress 12/01/03 to 11/30/06

Outputs
Aim 1. Glucose demand was increased by injecting phlorizin in a crossover experiment using 12 late-lactation cows (Bradford and Allen, 2005). Phlorizin caused a loss of 474 g glucose/d in urine and stimulated hepatic gluconeogenesis, as evidenced by increased mRNA abundance for 3 potentially rate-limiting gluconeogenic enzymes. However, neither feed intake nor feeding behavior were significantly altered by phlorizin, possibly because phlorizin also stimulated lipolysis, increasing delivery of FA to the liver. In a follow-up study, this lipolytic response was evident in early lactation cows as well, indicating that the presence of a catabolic state could not eliminate the confounding effects of phlorizin on lipid metabolism (Bradford and Allen, 2006). Aim 2. We directly tested the ability of phlorizin to lessen the hypophagic response to propionate in a 2x2 factorial design. As expected, intraruminal propionate infusion decreased feed intake, but phlorizin treatment had no effect on this response (Bradford and Allen, 2007). Aim 3. Thirty-two lactating Holstein cows were utilized in a crossover experiment with dietary treatments that differed only in dietary starch fermentability. High-moisture corn (highly fermentable) decreased feed intake 2.0 kg/d (P < 0.001) relative to dry, ground corn (less fermentable), consistent with prior observations. Increased starch fermentability also tended to decrease milk fat production (P = 0.06), and milk fat depression was dramatic in cows producing less than ~40 kg/d fat-corrected milk. Milk fat depression was highly correlated with greater concentrations of trans C18:1 FA in milk of low-producing cows fed the high moisture corn diet (Bradford and Allen, 2004). Additionally, propionate challenge tests conducted during a pre-trial period were used to evaluate the effects of propionate on plasma leptin concentrations. Leptin concentrations were decreased during the first 100 min following propionate infusion (P < 0.05), suggesting that the hypophagic effects of propionate are not mediated by leptin (Bradford, Oba, et al. 2006). We were unable to identify clear predictors of individual responses to propionate supply, despite the statistical power of a 32-cow crossover, suggesting that more mechanistic experiments are warranted. We conclude that short-term increases in glucose demand do not increase feed intake. One possible explanation is that increased delivery of FA to the liver stimulated by phlorizin administration increases hepatic FA oxidation, replacing the ATP that is lost as propionate is diverted from oxidation to glucose production.

Impacts
Fermentation characteristics of diets and pattern of propionate production in the rumen are easily manipulated and a greater understanding of propionate regulation of feed intake will allow diets to be formulated to maximize energy intake and milk yield. This will decrease the proportion of feed resources used to meet maintenance requirements, minimizing excretion of nutrients as waste products. However, despite the large effects of diet fermentability on DMI, no ration formulation program, to our knowledge, currently uses this to predict feed intake, which often limits milk yield. If our results are convincing, we envision that models will be adapted to predict hypophagic potential of diets based on concentration and fermentation rate of starch, which affects propionate flux to the liver following a meal.

Publications

  • Bradford, B. J. 2006. Propionate regulation of feed intake. Ph.D. dissertation, Department of Animal Science, Michigan State University.
  • Bradford, B. J., Gour, A. D., Nash, A. S., and Allen, M. S. 2006. Propionate challenge tests have limited value for investigating bovine metabolism. J. Nutr. 136:1915-1920.
  • Bradford, B. J. and Allen, M. S. 2007. Phlorizin administration did not attenuate hypophagia induced by intraruminal propionate infusion. J. Nutr. (in press).
  • Bradford, B. J. and Allen, M. S. 2007. Phlorizin induces lipolysis and alters meal patterns in both early and late lactation dairy cows. J. Dairy Sci. (accepted).
  • Bradford, B. J. and Allen, M. S. 2007. Short communication: Rate of propionate infusion within meals does not influence feeding behavior. J. Dairy Sci. (accepted) Allen, M.S. and Bradford, B. J. 2006. From the liver to the brain: increasing feed intake in transition cows. Pp. 115-124. Proc. 68th Meeting of the Cornell Nutrition Conference for Feed Manufacturers, Department of Animal Science, Cornell University, Ithaca, NY 14853-4801.
  • Bradford, B. J. and Allen, M. S. 2006. Propionate regulation of feed intake. J. Dairy Sci. 89S:49.
  • Bradford, B. J. and Allen, M. S. 2006. Phlorizin administration does not attenuate hypophagia induced by intraruminal Na propionate infusion. J. Dairy Sci. 89S:264.
  • Allen, M. S. and Bradford, B. J. 2006. Metabolic regulation of food intake in ruminants. J. Dairy Sci. 89S:120.
  • Bradford, B. J. and Allen, M. S. 2006. Propionate regulation of feed intake. J. Dairy Sci. 89S:49.


Progress 01/01/05 to 12/31/05

Outputs
Propionate was recently shown to increase leptin synthesis in rodents. To determine if a similar effect occurs in ruminants, propionate was administered to lactating dairy cows. In experiment 1, 31 cows were given an intrajugular propionate bolus (1.04 mmol/kg body weight), increasing plasma propionate from 0.2 to 6.0 mM and plasma insulin from 7 to 80 micro U/mL. Plasma leptin concentration decreased from 2.1 ng/mL before bolus to 2.0 ng/mL after dosing (P < 0.05) with no differences in leptin concentrations at 20, 50, and 100 minutes post-bolus (P > 0.05). In experiment 2, 12 cows were used in a duplicated 6x6 Latin square design to assess the dose-response effect of ruminal propionate infusion on plasma leptin concentration. Iso-osmotic mixtures of sodium propionate and sodium acetate were infused continuously for 18 h (21.7 mmol sodium VFA/min); treatments included 0, 20, 40, 60, 80, or 100% of VFA from propionate. Effects on plasma leptin were assessed at the end of the 18-h infusions. Increasing the proportion of propionate in the infusate linearly increased plasma propionate concentration from 0.18 to 0.33 mM (P < 0.001) and linearly increased plasma insulin concentration from 6.7 to 9.1 micro U/mL (P < 0.05). However, plasma leptin concentration was not affected by treatment. Propionate does not stimulate leptin secretion in lactating dairy cows.

Impacts
Fermentation characteristics of diets and pattern of propionate production in the rumen are easily manipulated and a greater understanding of propionate regulation of feed intake will allow diets to be formulated to maximize energy intake and milk yield. This will decrease the proportion of feed resources used to meet maintenance requirements, minimizing excretion of nutrients as waste products. However, despite the large effects of diet fermentability on DMI, no ration formulation program, to our knowledge, currently uses this to predict feed intake, which often limits milk yield. If our results are convincing, we envision that models will be adapted to predict hypophagic potential of diets based on concentration and fermentation rate of starch, which affects propionate flux to the liver following a meal.

Publications

  • Allen, M.S., Bradford, B.J., Harvatine, K.J. 2005. The cow as a model to study food intake regulation. Ann. Rev. Nutr. 25:523-547.
  • Bradford, B. J., Allen. M. S. 2005. Phlorizin administration increases hepatic mRNA abundance for gluconeogenic enzymes but not feed intake in late-lactation dairy cows. J. Nutr. 135:2206-2211.
  • Bradford, B. J., Oba, M., Ehrhardt, R., Boisclair, R., Allen, M. S. 2005. Propionate is not an important regulator of plasma leptin in dairy cows. Domest. Anim. Endocrinol. 2005 Jul 4; [Epub ahead of print]
  • Bradford, B. J., Allen, M. S., Oba, M., Ehrhardt, R., Boisclair, Y. R. 2005. Propionate does not stimulate lepting secretion in lactating dairy cows. 2005 Experimental Biology meeting abstracts. FASEB J. 19: Abstract #6229.
  • Bradford, B. J., OToole, A. D., Nash, A. S., Allen, M. S. 2005. Validation of propionate challenge test methodology. J. Dairy Sci. 88(Suppl. 1):249.


Progress 01/01/04 to 12/31/04

Outputs
Flux through gluconeogenic pathways may be an important factor regulating dry matter intake in lactating dairy cows. To determine if increased glucose demand affects intake or hepatic metabolism, lactating Holstein cows were treated with phlorizin or propylene glycol (carrier) for 7-d treatment periods. Twelve multiparous cows (mean 269 d in milk) were randomly assigned to treatment sequence in a crossover design and were adapted to a common diet for 7 days prior to the beginning of the experiment. Phlorizin injected subcutaneously at 4 g/d caused glucose excretion in urine at the rate of 474 g/d. While phlorizin caused a decrease in lactose synthesis and milk production (both P < 0.01), dry matter intake and 3.5% fat-corrected milk production were not altered by treatment. A net deficit of 383 g/d of glucose for phlorizin relative to control was likely replaced through increased gluconeogenic flux. Molar ratio of insulin:glucagon was decreased 17% by phlorizin (P < 0.001) and hepatic phosphoenolpyruvate carboxykinase mRNA abundance tended to increase (P = 0.08). In addition, abundance of pyruvate carboxylase mRNA in liver was greater with phlorizin treatment (P < 0.001), suggesting that retention of glucose precursors may be involved in regulation of gluconeogenesis. Late-lactation dairy cows adapted quickly to an increase in peripheral glucose demand. Adaptation mechanisms likely included enhanced gluconeogenic capacity, while dry matter intake was not immediately altered.

Impacts
Fermentation characteristics of diets and pattern of propionate production in the rumen are easily manipulated and a greater understanding of propionate regulation of feed intake will allow diets to be formulated to maximize energy intake and milk yield. This will decrease the proportion of feed resources used to meet maintenance requirements, minimizing excretion of nutrients as waste products. However, despite the large effects of diet fermentability on DMI, no ration formulation program, to our knowledge, currently uses this to predict feed intake, which often limits milk yield. If our results are convincing, we envision that models will be adapted to predict hypophagic potential of diets based on concentration and fermentation rate of starch, which affects propionate flux to the liver following a meal.

Publications

  • Bradford, B. J. and M. S. Allen. 2004. Milk fat responses to a change in diet fermentability vary by production level in dairy cattle. J. Dairy Sci. 2004 87: 3800-3807
  • Bradford, B. J. and M. S. Allen. 2004. Increasing glucose demand increases hepatic pyruvate caroxylase mRNA concentration but not feed intake in late-lactation dairy cows. J. Anim. Feed Sci. 13:377-380.
  • Bradford, B. J. and M. S. Allen, M. S. 2004. Increasing dietary starch fermentability causes milk fat depression in low-producing, but not high-producing cows. J. Dairy Sci. 87(Suppl. 1):308.