Transcript The effects of enhanced NDF digestibility of corn silage

The Role of VFAs
in Lipid and Carbohydrate Metabolism
Barry J. Bradford1 and Michael S. Allen2
1Kansas
1Contact
State University, 2Michigan State University
information:
Barry Bradford, Associate Professor
135 Call Hall
[email protected]
Manhattan, KS 66506
1-785-532-7974
Topics
• Metabolism of VFA:
substrate effects
• The concept of bioactive nutrients
• Direct signals
• Endocrine effects
• Neuronal effects
• Conclusions
Different VFAs play different roles
Microbial
metabolism
Cellulose
Starch
(primarily)
Acetate
(more)
Propionate
Fatty acids
+ ATP
Glucose
Host animal
metabolism
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
Ash and Baird, 1973, Biochem. J. 136:311
mol product /min per g of tissue
4.0
3.5
3.0
2.5
Acetate
Propionate
Butyrate
2.0
1.5
1.0
0.5
0.0
Rumen
Liver
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
G-protein coupled receptors can mediate
effects of short-chain fatty acids
Acetate
GPR43
Propionate Butyrate
GPR41
Lactate
GPR81
Intracellular Signal Transduction
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
Donkin et al., 2009
Relative mRNA abundance
3.5
3.0
2.5
2.0
Saline
Acetate
1.5
Propionate
1.0
0.5
0.0
PEPCK
G-6-Pase
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
Benson et al., 2002 J. Dairy Sci. 85:1804
Feeding
Diurnal variation in plasma insulin and metabolites for
mid-lactation cows offered feed ad libitum
Allen et al., 2005 Annu. Rev. Nutr. 25:523
1.4
NEFA, mM
Acetate, mM
1.6
1.2
1
0.8
0.6
0.4
0
4
8
12
16
20
24
-1
16
Glucose, mg dl
-1
200
150
18
Insulin, µIU ml
250
14
12
10
8
6
0
4
8
12
Time, h
16
20
24
0
4
8
12
16
20
24
0
4
8
12
16
20
24
66
64
62
60
58
56
54
52
Time, h
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
Oba and Allen, 2003 J. Nutr. 133:1094
NEL intake, Mcal/12 h
35
30
25
20
15
10
5
0
Linear effect P < 0.0001
Infusion 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
0
33
67
% propionate
100
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
Feed intake of sheep, g/3 h
Anil and Forbes, 1988
450
400
350
300
250
200
150
***
100
50
0
Saline
Prop
Saline + Vagotomy
Prop + Vagotomy
Connection from the liver to the brain: hepatic vagus
Satiety
Hunger
ATP
Fuels oxidized in ruminant liver
•
Fatty acids
NOT:
Diet
Adipose
•
•
•
•
Amino acids
• Lactate
• Glycerol
• Propionate
Glucose
• Acetate
Model by which propionate may stimulate satiety
insulin
(+)
ketones
glucose
(-)
(-)
propionate
flux to liver
acetyl CoA
(+)
(+)
oxidation
increased diet
fermentability
(+)
(+)
feed intake
(-)
satiety center
NEFA
Hypophagic effects of propionic acid increased
with hepatic acetyl CoA concentation
Stocks and Allen, 2011
TRT*Acetyl CoA
Interaction, P = 0.07
Propionate regulation of feed intake by hepatic oxidation?
• 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
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.