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 bbradfor@ksu.eduManhattan, 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.