The Role of VFAs in Lipid and Carbohydrate Metabolism Barry J. Bradford 1 and Michael S. Allen 2 1...
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Transcript of The Role of VFAs in Lipid and Carbohydrate Metabolism Barry J. Bradford 1 and Michael S. Allen 2 1...
The Role of VFAs in Lipid and Carbohydrate Metabolism
Barry J. Bradford1 and Michael S. Allen2
1Kansas State University, 2Michigan State University
1Contact information:Barry Bradford, Associate Professor135 Call Hall [email protected], KS 66506 1-785-532-7974
• Metabolism of VFA: substrate effects
• The concept of bioactive nutrients• Direct signals• Endocrine effects• Neuronal effects• Conclusions
Topics
Different VFAs play different roles
Cellulose
(primarily)Acetate
Fatty acids+ ATP
Starch
(more)Propionate
Glucose
Microbialmetabolism
Host animalmetabolism
Butyrate: Unique role as the preferred energy source for ruminal epithelium.
Minor VFA play a major role in physiology
• Acetate comprises 50 – 75% of total VFA produced in the rumen, propionate 15 – 45%, butyrate 1 – 12%.(Sutton et al., 2003)
• Propionate and butyrate often have more dramatic effects on metabolic physiology
Ash et al., 1964
Uptake of VFA is tissue-specific
Rumen Liver0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0AcetatePropionateButyrate
mol
pro
duct
/m
in p
er g
of ti
ssue
Ash and Baird, 1973, Biochem. J. 136:311
Bioactive Nutrients
• Nutrients that influence physiology independent of substrate effects.
• This typically occurs through activation of cell membrane receptors or nuclear receptors resulting in:– Altered cellular function– Release of endocrine factors– Stimulation of neuronal signals
Substrate vs. receptor-mediated nutrient effects
Substrate effects• Impact limited to tissues
utilizing the nutrient• Interactions with other
nutrients key• Responses in different
metabolic state or life stages dependent on metabolism of nutrient
Receptor-mediated effects• Impact dependent on
distribution of receptor• Interactions with hormones
may be critical• Responses in different
metabolic states or life stages dependent on expression of receptor
GPR81GPR41
GPR43
Acetate Propionate Butyrate Lactate
Intracellular Signal Transduction
G-protein coupled receptors can mediate effects of short-chain fatty acids
Acetate and propionate promote adipogenesis in cultured pre-adipocytes
Hong et al., 2005
Red = Oil red O lipid stain
Acetate and propionate suppress lipolysis through GPR43 in mice
Ge et al., 2008
Importance in cattle?
• GPR41 and GPR43 were not detected in adipose tissue of cattle (Wang et al., 2009)
• Propionate increased leptin secretion in mice, but not in cattle (Bradford et al., 2006)
• Role in liver metabolism??
VFA can stimulate expression of gluconeogenic genes in pre-ruminant calves
PEPCK G-6-Pase0.0
0.5
1.0
1.5
2.0
2.5
3.0
SalineAcetatePropionate
Rela
tive
mRN
A a
bund
ance
Donkin et al., 2009
Importance in cattle?
• In most experiments evaluating signaling effects of VFA, obvious effects are seen only in fasted animals or pre-ruminant calves.
• Basal concentrations of VFA in fed ruminants may be adequate to activate these receptors constitutively.
Endocrine effects of VFA
• VFA can also impact metabolism by altering secretion of metabolic hormones
Propionate potently stimulates insulin secretion
Bradford et al., 2006
Propionate flux to the liver increases dramatically at meals
Feeding
Benson et al., 2002 J. Dairy Sci. 85:1804
Diurnal variation in plasma insulin and metabolites for mid-lactation cows offered feed ad libitum
Allen et al., 2005 Annu. Rev. Nutr. 25:523
Propionate depresses feed intake compared to acetate
• Infusion of propionate into the mesenteric vein of steers decreased feed intake but infusion of acetate at similar rates did not (Elliot et al., 1985)
• Hepatic extraction of propionate > 70% of total supply (Reynolds et al., 2003)
• Ruminant hepatocytes have high activity of propionyl CoA synthetase but not acetyl CoA synthetase (Ricks and Cook, 1981; Demigne et al., 1986)
Propionate vs. acetate
05
101520253035
0 33 67 100
Oba and Allen, 2003 J. Nutr. 133:1094
% propionate
NEL intake, Mcal/12 hInfusion of mixtures of propionate and acetate at 25 mmol/min from 2 h before feeding until 12 h after feeding
NEL intake intake = feed + VFA
Linear effect P < 0.0001
Is hypophagia from propionate insulin-dependent?
• Propionate has depressed DMI without altering plasma insulin (Farningham and Whyte, 1993; Frobish and Davis, 1977)
• Insulin’s putative effects on DMI are through receptors in the CNS, yet hepatic vagotomy eliminated response to propionate infusion
• Hyperinsulinemic-euglycemic clamps generally do not depress energy intake (Mackle et al. 1999; Griinari et al. 1997; McGuire et al. 1995)
Propionate’s effects on intake are nerve-mediated
Saline Prop Saline + Vagotomy Prop + Vagotomy0
50
100
150
200
250
300
350
Feed intake of sheep, g/3 h
***
Anil and Forbes, 1988
Connection from the liver to the brain: hepatic vagus
Satiety
Hunger
ATP
Fuels oxidized in ruminant liver
• Fatty acids• Diet• Adipose
• Amino acids• Lactate• Glycerol• Propionate
• Glucose• Acetate
NOT:
Model by which propionate may stimulate satiety
(+)insulin
(-)
(-)
(+)
NEFAacetyl CoA
satiety center
(+)
(-)feed intake
propionate flux to liver
(+)
(+)
increased diet fermentability
oxidation
ketonesglucose
Hypophagic effects of propionic acid increased with hepatic acetyl CoA concentation
TRT*Acetyl CoA Interaction, P = 0.07
Stocks and Allen, 2011
• Propionate is a primary end-product of ruminal starch digestion
• Ruminal production rates vary greatly between diets, primarily because of differences in starch fermentability
• Can be produced and absorbed at very high rates; rapidly taken up by the liver
• Once propionate is absorbed it is metabolized almost exclusively by the liver
• Hypophagic effects of propionate are eliminated by hepatic vagotomy
Propionate regulation of feed intake by hepatic oxidation?
Take-home points
• VFA can influence ruminant metabolism through substrate-level effects, by directly altering cellular function, by altering hormone secretion, or by activating neural signals.
• As we learn more about functional roles of VFA, these concepts will be used to improve diet formulation to support health and productivity.
Thank you!
Sweet ride.