This document discusses the interaction of long-term and short-term controls of feed intake in ruminants. It proposes that the liver plays a key role in sensing energy status and signaling brain feeding centers via the Hepatic Oxidation Theory. Specifically, it suggests that the liver integrates signals from fuels oxidized in the tricarboxylic acid cycle to both stimulate and inhibit feeding behavior through various hormonal and metabolic factors that change with diet and physiological state over time.
2. Long-term vs. short-term controls
• Homeorhetic control: long-term
– Coordinated changes in metabolism of body tissues
necessary to support a physiological state
– Example: pregnancy, lactation
• Homeostatic control: short-term
– involves maintenance of physiological equilibrium
– Example: temperature regulation, glucose regulation,
feeding behavior
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Bauman and Currie, 1980 J Dairy Sci 63:1514
3. Transition from pregnancy to lactation
• Spare glucose for fetus in late pregnancy
• Increase energy (fat) content of colostrum and early
milk
• Prepare for the large increase in glucose demand for
milk production following calving
• Provide alternate fuels for tissues when plasma
glucose decreases as milk yield increases
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6. Growth hormone / IGF-1
6
Doepel et al., 2002 J. Dairy Sci. 85:2315
High GH / Low IGF-1
associated with insulin
resistance
7. NEFA
7
Doepel et al., 2002 J. Dairy Sci. 85:2315
Lipolysis increases from
decreased plasma insulin
concentration and
increased insulin
resistance of tissues
14. Initiation of meals: inhibitory signals subside
and stimulatory signals increase
Time between meals
Signalstrength
Stimulatory signals
Inhibitory signals
15. Cessation of meal: inhibitory signals intensify
and stimulatory signals diminish
Meal length
Signalstrength
Stimulatory signals
Inhibitory signals
18. • Mechanisms controlling feed intake
– Adequate supply of nutrients
– Prevent overconsumption
• Signals integrated in brain feeding centers
• Liver is likely a primary sensor of energy status
– Signal related to oxidation of fuels
– Integrates many physiological effects
• Signal from liver is both inhibitory and stimulatory
• Fuel supply in blood
– Diet x physiological state
– Energy intake x energy partitioning
19. Hepatic Oxidation Theory
• Liver transmits signals to brain feeding centers via vagal
afferents
• Feeding behavior is affected by firing rate of the nerve
– Decreased firing rate inhibits feeding
– Increased firing rate stimulates feeding
• Firing rate is affected by oxidation of fuels
– Increased oxidation decreases firing rate: inhibiting
– Decreased oxidation increases firing rate: stimulating
Allen et al., 2009 J. Anim. Sci. 87: 3317
Hepatic Oxidation Theory
20. Fuel sensing: liver
• Metabolizes a variety of fuels derived from both the diet
and tissues
• Unique advantage of sensing energy supply relative to
energy demand
21. • Oxidation through acetyl CoA in TCA cycle:
– NEFA
– Amino acids
– Lactate
– Glycerol
– Propionate
• Stimulate oxidation of acetyl CoA
– Propionate, especially within meals
– Amino acids, lactate, glycerol
Fuel oxidation in the ruminant liver
22. Stimulation of hepatic oxidation
• Need supply of acetyl CoA to be oxidized
– NEFA is primary source of acetyl CoA
• Need TCA intermediates to spin the cycle
– Propionate is primary supply of TCA intermediates during
meals
– …all fuels are oxidized in the TCA cycle through acetyl CoA
– Increased glucose demand decreases TCA intermediates
– Decreased glucose demand increases TCA intermediates
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24. Fuel supply:
interaction of diet and physiological state
• Fuels available for hepatic oxidation are affected by:
– Plasma insulin concentration
– Insulin sensitivity of tissues
– Somatotropin and growth factors
– Leptin
• Affects energy intake and partitioning
26. Diurnal variation in plasma concentrations of
insulin and NEFA in the lactating cow
0
5
10
15
20
25
30
0
50
100
150
200
250
300
0 4 8 12 16 20 24
Insulin
NEFA
Insulin,µIUml-1
NEFA,µM
Time (h)
r = 0.34
P < 0.001
Data from Oba and Allen, 2003 J. Dairy Sci. 86:174
27. Variation among cows in DMI response to
increased ruminal starch fermentation
Data from Bradford and Allen, 2004 J. Dairy Sci. 87:3800
-7 -6 -5 -4 -3 -2 -1 0 1
Change in DMI (kg/d, HM-DG)
28. Preliminary plasma insulin predicted DMI
response to a more fermentable diet
Bradford and Allen, 2007 J. Dairy Sci. 90:3838
29. Insulin response to glucose infusion predicted
DMI response to a more fermentable diet
Bradford and Allen, 2007 J. Dairy Sci. 90:3838
30. Insulin, diet fermentability, and HOT
• Gluconeogenesis is down-regulated with higher mean [Insulin]plasma
• Propionate produced from a more fermentable diet is oxidized
sooner within meals, causing satiety
• Smaller meals result in decreased daily DMI
• No correlation between preliminary [Insulin]plasma and insulin
response during glucose infusion
• Greater insulin response results in decreased supply of NEFA to liver,
causing hunger sooner
31. Hypophagia during the periparturient period
Doepel et al., 2002 J. Dairy Sci. 85:2315
32. Hypophagic effects of propionic acid increased
with hepatic acetyl CoA concentration
Treatment x AcCoA
Interaction, P = 0.07
Stocks and Allen, 2013 J. Dairy Sci. 96:4615
33. Acetyl CoA availability
35
R2
= 0.54; P < 0.01 R2
= 0.38; P = 0.02 R2
= 0.31; P = 0.04
Greater insulin sensitivity = greater DMI?
Piantoni et al., 2014
35. Summary
• Mechanisms controlling energy intake and partitioning are:
• Multiple, entwined, and inseparable
• Affected by diet and physiological state
• The liver is likely an important sensor of energy status:
• Signaling brain feeding centers to stimulate and inhibit feeding
• Integrating short and long-term mechanisms
• Brain feeding centers integrate all signals and dominant
mechanisms controlling feeding change with diet and
physiological state
36. Hepatic oxidation is the only proposed mechanism for control
of feed intake that can accommodate both differences in fuels
absorbed and sites of absorption across species while
remaining consistent with intake responses to diets.
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Feed intake over the first 4 h after feeding for cows in the postpartum period was positively related to:
Decrease in hepatic acetyl CoA concentration
Decrease in plasma NEFA concentration
Not related to initial concentrations of NEFA, BHBA, or insulin
Change in plasma NEFA concentration was positively related to change in hepatic acetyl CoA content
Greater insulin sensitivity = greater DMI?