exam 2 ansc 301
Hepatic Oxidation Theory of Intake Regulation
- Blood from the gut goes first to the liver, and the liver is extensively involved in metabolism - Logically placed to observe the amount of energy and nutrients available - Theory proposes that energy state of the liver is sensed (Ratio of ATP:ADP) and a signal sent to the brain by hepatic vagus nerve
Glucose is a very important nutrient in the body
1.Blood glucose - most important vehicle for moving energy in the body in absorptive and non-absorptive state (fed and fasted) 2.Sources of blood glucose vary with: - Type of GI Tract - Diet - Time after eating
Glucose is used (Metabolized) in both catabolic and anabolic pathways
1.Catabolism a) Glycolysis: Glucose -> Pyruvate b) Oxidation: Pyruvate -> CO2 + H2O c) Pentose Phosphate: Glucose ->NADPH 2.Anabolism a) Glycogen synthesis b) Lipid synthesis
Examples of Nutrient Partitioning/ Directing
1.Early Growth -Bone and Muscle 2.Late Growth -Muscle and adipose tissue 3.Late Pregnancy - Gravid uterus and mammary gland 4.Early Lactation -Mammary gland for milk synthesis 5. Nutrient "Repartitioning" - Movement from one tissue to another - Occurs when nutrients supply is low
To Maintain "Metabolic Set-Point" long-term intake must be matched with nutrient requirements
Important Factors 1. Pull of Nutrients (Nutrient Demand) 2. Amount of body fat 3. Internal stresses (ex. Fever or disease) 4. Environment (Temperature or day length) If input > output Positive E balance (gaining weight). If input < output Negative E balance (losing weight).
You can also calculate heat production (HP) by difference if you know ME and NER
ME = HI + NEm +NER Total heat produced by an animal HP = total HI + NEm then ME = HP + NER HP = ME - NER How do you get NER? - Weigh milk or eggs produced and determine energy density (bomb calorimeter) - Comparative Slaughter where you harvest one portion of group and determine carcass energy and the feed for a period of time and then determine energy in rest
Requirements are normally separated by function
Maintenance Reproduction Pregnancy Lactation Growth Work
Glucose is absorbed into the cell by SGLT1 and move out of the cell through GLUT2
Transporters controls what and how much of a nutrient is taken up by the cell •Transporters are regulated in both the short and long term •Some CHO's can't be absorbed and end up in the hindgut where they may be fermentedEx. low calorie sweeteners
Long-Term Systems are thought to change the Threshold of Short Term Systems. This might mean an over-fat animal? A.Become hungry sooner after a meal B.Takes longer to become full during a meal C.Takes longer to become hungry after a meal D.Has increased insulin sensitivity
c
There are multiple energy units, the Joule (J) is the international unit and calorie (cal) is older unit used in the USA
cal = heat required to increase the temperature of one gram of water from 14.5 to 15.5C 1 cal = 4.184 J (don't memorize this!) •1000 calories (1 kcal) = 1 "Calorie"
how to regulatory system works
energy blance -> gut liver cns receptors (sense status)->send signal Hypothalamic centers (integrate signals) -> change # or size of meals Energy intake (+-) -> back to energy balance
Complete oxidation of glucose yields
~36 ATP •Efficiency of energy capture as ATP is ~39%, with remaining energy lost as HEAT
Two Examples of Leptin Disruption: No Leptin or No Leptin Receptor
•ob/ob mouse -Defect is the leptin gene (ob gene) -Do not make biologically active leptin -No feedback with increased fat in adipose tissue, continues to eat •db/db mouse -Defect in the leptin receptor (db gene) -Secrete plenty of leptin, but lack the ability torespond to it
Fat synthesis occurs next and serves as long-term energy storage
"De novo" fat synthesis -Need both carbon and reducing equivalents (NADPH) -Increased by insulin (Will discuss pathways later!) -Can't get glucose back!
Glucose can be completely oxidized to CO2 to yield more energy
- Before complete oxidation pyruvate must move from the cytosol into the mitochondria - Pyruvate provides two essential intermediates for the TCA cycle: -acetyl CoA -oxaloacetate
Some animals have requirement that are very close to maintenance
- Adult males outside of breeding season - Castrated male sheep used for wool production only - Females when not pregnant or lactating
Direct Calorimetry is/was the Gold Standard to directly measure heat production (HP)
- Animal in insulated chamber - The heat produced is observed as how much it takes to maintain temperature of the chamber - Also determined energy lost in methane
Many important tissues preferentially oxidize glucose for energy:
- Brain - Red blood cells - Leucocytes (immune cells) - Gonads-Gravid uterus Glucose is under "Homeostatic" regulation -Moderate acute hypoglycemia- lower brain function -Severe hypoglycemia- coma or even death -High blood glucose: Tissue damage -Brain can switch to ketones in long-term fast(Ketones made from fat)
3. Endocrine Control of Intake A. Insulin & Glucagon
- Glucose is main absorbed metabolite in non-ruminants - Glucose stimulates insulin secretion from the pancreas - High insulin and low glucagon after a meal stimulates satiety centrally - But, low blood glucose stimulates hunger -High Insulin can result in increased intake in the long run because blood glucose drops and become hungry sooner (Basis of Atkins Diet)
Net energy is broken into NE for Maintenance and NE for other specific functions.
- NE is the energy retained. Everything else is heat increment. - You have to do this as the heat production for each is different so each has own NE value.
Digestible energy (DE) is widely used in non-ruminants
- Nonruminant has very small CH4 losses and relatively constant losses in urine and heat increment of feeding - Can Directly Measure!!! Less Guessing or "Mathematical Predictions" Digestibility more consistent in non-ruminant • Not good for ruminants because fails to account for methane loss in ruminants and other metabolic losses
Factors Impacting Intake: 3. Other Environmental and Physiological Factors
- Stress - Disease
Signals Communicating How many Nutrients are Available 3. Endocrine/Neuroendocrine Signals
- blood and central nervous system hormones e.g. insulin, gut hormones
Signals Communicating How many Nutrients are Available 2. Chemical Signals
- blood glucose - rumen VFA - digesta pH - digesta osmolarity
Signals Communicating How many Nutrients are Available 1. Physical Signals
- gut fill
When Does Insulin Resistance Occur
-During inflammation and disease -During fasting and early lactation -In obese animals •Results in high blood glucose, fatty liver, and fat in muscle tissue •How to test -Random plasma glucose -Fasting plasma glucose -Glucose tolerance test (GTT) •Give an oral dose of glucose and measure plasma glucose and insulin
Factors Impacting Intake: 1. Sensory Stimulation
-Factors sensed in process of locating and consuming food -All senses: sight, smell, taste, texture, temperature, sound etc. 1. Food characteristics -Palatability 2. Other external stimuli-Other animals, "feeding time" -Social pressure 3. Environmental discomfort -Hot, muddy, stress, lack of space
Glycogen Synthase- is the key regulated enzyme that adds one glucose at a time to the end of the chain when making glycogen
-Insulin•Turns glycogen synthesis on by phosphorylation -Allosteric control (Feed Forward Regulation) •High cellular Glucose 6-P increases rate This is a cycle:Make Glycogen then break it down. Energetically wasteful, but very small loss
Leptin
-Synthesized and secreted from Adipose Tissue - More when cell is larger (more fat stored)
CNS Centers Regulate the Beginning and End of Each Meal
-The Faster a SATIETY CENTER is turned ON during a meal the smaller the meal will be -The Sooner the HUNGER CENTER is turned ON after meal the more meals consumed per day
Energy requirement is always considered first in balancing a diet
1. All dietary constituents except minerals and water contain energy 2. Feed ingredients mostly fed for energy (e.g. corn, forages) account for most of ration in terms of weight and cost 3. Rate of energy supply and utilization dictates use of other nutrients e.g. protein, B vitamins. That is, energy is the pacesetterfor requirements of other nutrients
Factors Impacting Intake:
1. Sensory Stimulation 2. Appetite 3. Other Environmental and Physiological Factors
Fasting (Post-absorptive)- Where do we get glucose?
1st. Break down glycogen (Glycogenolysis) 2nd- Make glucose from glucogenic precursors (Gluconeogenesis)
TDN (total digestible nutrients) is the unit most commonly used to measure feed energy in the USA and is similar to DE
= Digested Protein + Digested CHO + (Digested Fat x 2.25) • Can calculate based on feed analysis and expected digestibility • Several disadvantages especially for feeds which vary widely in digestibility (forages) • Major disadvantage - failure to account for variations in energy losses in urine, CH4 and heat, especially in ruminants!!!
Total Heat Production
= HI + NEmaint 1. Heat increment of feeding Heat production (HI) resulting from the ingestion, digestion, and metabolism of feed 2. Nemaint Heat production resulting from maintenance of basal state (more on this later)
Basal metabolism is affected by:
A.Body size Heat Production per metabolic body size is pretty similar between animals B.Species C. Age & Neuroendocrine Factors
Maintenance and Non-Productive Requirements are a combination of:
Basal metabolism, Muscular work, Temperature regulation
Net energy (NE) value of a feed accounts for all losses!!!
But in reality is extremely difficult to directly measure -Commonly used in ruminants in US, but are based on predictions of conversion of DE, TDN or ME to NE!!! -Need separate values depending on what the energy is used for (NEM,L,G)
3. Endocrine Control of Intake: B. Gut Peptides as Food Sensors
CCK and GLP1 Cholecystokinin and glucagon like peptide 1- Secreted by intestine in response to fat and protein- Induces satiety in the brain Ghrelin: - Secreted from stomach before a meal - Stimulates hunger
Metabolizable energy (ME) is energy available to tissues and is widely used in Europe
DE - urine energy - gas energy Ruminants: ME ≈ 0.82 DE (higher methane loss) Nonruminants: ME ≈ 0.95 DE • Mandatory for poultry (cannot get DE because feces and uric acid mixed) • Takes account of urine and CH4 losses, but not heat increment -Reality is that it is difficult to directly measure so we predict conversion based on DE (or TDN) using previously determined conversions ex. ME = (1.01 x DE - 0.45) + 0.0046 x (EE-3)
Indirect Calorimetrycalculates heat production (HP) and is based on the stoichiometry of oxygen used and CO2 and energy produced
Determine Respiratory Quotient-RQ = CO2 produced/O2 consumed RQ is 1.0 for CHO 0.7 for fat 0.81 for protein -Based on RQ and total oxygen consumption you calculate energy oxidized -Based on amount and source oxidized can calculate Heat Produced
Digestible energy (DE)
Energy that was not lost in feces GE - fecal energy - Have to measure energy in feces by weighing and subsampling feces then bomb calorimeter on the feces
Net energy (NE)
Energy that was used to keep the animal alive or retained in the body or products ME - heat increment of feeding Subdivided into NEmaintenance & NERetained
NER is the Energy in the product/work. Energy lost is heat increment (HI)!
Example: Net Energy of Lactation - Determine the amount of energy in the milk produced -NEL is the energy retained in milk - The energy lost in making milk is Heat increment (HI)!!! Ex. Liver Gluconeogenesis and mammary Lactose synthesis
The "Laws of Thermodynamics" apply to the entire world, including animal nutrition!
First law:Energy can be neither created nor destroyed Corollary 1 - Energy can be inter-converted between different forms Corollary 2 - Thermal energy (heat) cannot be converted to other forms in the body Second Law:Entropy increases - Energy is lost as Heat in metabolic reaction
Extra glucose is first stored as glycogen for later use
Glycogenesis = glycogen synthesis -Predominantly increased by insulin and availability of Glucose-6-P -Can get glucose back out
Heat increment of feeding
Heat production resulting from the ingestion, digestion, and metabolism of a given amount of feed (increment above maintenance heat) - Remember metabolism had a ΔG ≈ ΔH
What do you think happens when you give leptin to the ob/ob mouse? A.Increase weight gain B.No change in weight gain C.Increased insulin sensitivity D.Decreased intake
Leptin Infusion Corrects Obesity in ob/ob Mouse
1.Basal metabolism is minimal metabolic rate (measured as heat production)
Measurement requires: • post-absorptive state • minimal physical activity • minimal psychic stress
Physical fill sensors regulating intake
Mechanical (stretch) receptors - Located in gut wall - Send nerve signal to brain when activated Gut Fill is dependent on: 1. Gut Capacity- not well correlated with BW - dependent on other things in body - can stretch or shrink 2. Rate and extent of digestion 3. Rate of passage of feed Can use Physical Fill to limit intake (ex. Fiber in companion animals and gastric bypass surgery).
What comes first- energy need or intake??
Normally need drives intake, but intake can limit production/growth
Are Defects in ob and db Genes the Cause of Obesity in Humans?
Only in a few rare cases 1. Obesity and intake regulation in humans and other animals is more complex - it is a polygenic trait. 2. Human food intake behavior also has substantial cultural, social and psychological influences.
2. Chemostatic Controls Regulating Intake
Principle: nutrients concentration is sensed -chemoreceptors (stimulated by nutrients) -gut, blood vessels, or brain Signal sent to the hypothalamus intake centers - Low blood glucose in non -ruminants - High VFA in the rumen and blood - High dissolved compounds in duodenum- Imbalanced blood AA - High plasma free fatty acids (non-esterified) - Signal to the brain either by second endocrine hormone or nerve impulse (afferent signal)
Energy sets the requirement for other nutrients, so a low energy diet has a lower protein requirement because you have lower maximal growth
This is called the "Broken-Stick" Model. The requirement is at the break point
Gross energy (GE)
Total energy content of a given weight of feed, measured as its heat of combustionby bomb calorimetry
Key principle: Animals normally eat the quantity of food required to meet their energy needs!!!!!
Will eat less than requirement if stomach becomes full before consuming enough energy! Examples: 1.Pigs fed diets with added sawdust 2.Feeding high-fat vs low-fat milk to baby pigs
Homeorhesis
coordination of metabolism in support of a dominant physiological process -Priorities partitioning of nutrients -Directs nutrients in a certain "direction"
Which of the following will increase daily intake? A.Decrease meal size B.Increase interval between meals C.Decrease number of meals D.Increase meal size
d
"Dilution of Maintenance"
increases the proportion of energy used for production and thus increases conversion of feed to product (efficiency) Dilution of Maintanence explains most of the increases in efficiency in modern production
Homeostasis
maintenance of the normal body state
CNS intake control "Centers" are located in the hypothalamus
• Feeding or Hunger "centers" - lateral hypothalamus • Satiety "centers" - ventromedial nucleus (VMN)
Intake is Regulated Both by Short-Term and the Long-Term Systems
• Short-Term- controls size and frequency of meals within day Daily Intake = Number meal x meal size Meals are based on Hunger and Satiety • Long-term- regulates intake over several days or weeks Based on energy balance Goal- Maintain ideal body weight
Maintenance requirement is the amount needed to maintain an animal in zero balance of that nutrient (Not gaining or losing)
• Strict definition applies only to mature non-productive animal (not pregnant or lactating) • Other non-productive requirements are also needed to survive in the animals environment Ex. Walking from pasture to barn/water, maintaining body temperature in cold environment. • Normally combine Maintenance and non-productive into the same requirement
Factors Impacting Intake: 2. Appetite
• The level of desire for food Balance of: •Hunger- the desire to eat •Satiety- no desire to eat Determined by integration of many signals
TCA Cycle = Krebs
•1st step: condensation of Acetyl-CoA with OAA •Produces CO2, GTP, and NADH (reduced coenzymes) •Other carbon sources are also oxidized in the TCA (VFA's, AA C-skeletons, and fatty acids)
The GI Tract also regulates metabolism
•CCK, GIP ("Glucose inhibitory peptide" or glucose-dependent insulinotropic peptide), GLP -1 (Glucagon like peptide 1) -Increase insulin secretion by lowering the plasma glucose concentration required to stimulate insulin secretion - If you IV glucose, sometimes need to also give insulin because will not have a big insulin response •Ghrelin -Stimulates growth hormone secretion
Increasing Pull of Nutrients from Peripheral Blood Increases Intake
•Depends on physiological state •Genetics •Productivity
Physiological Fuel Values (PVFs) or "Atwater Factors" are what are used in human nutrition in the USA (food labels etc.)
•Developed in early 1900's and still used because is simple and pretty close to right •Based on GE, digestibility in dogs, and correction for urine secretion •Result is pretty similar to a ME •Work well when digestibility is predictable Atwater Specific Factor System (1955) Different values for each food. Accounts for difference in AA's and types of CHO
Bioenergetics is the study of energy supply, utilization, and loss in animals
•Energy is the capacity for performing work •Many types of work- chemical, mechanical, electrical, or osmotic work •Many types of energy- thermal, chemical, electrical, radiant, nuclear, magnetic, etc.) Nutrients contain chemical energy which is yielded upon chemical breakdown and can be used in the body to perform work
TCA Cycle is regulated to maintain constant energy status
•Formation of acetyl-CoA from PyruvatePyruvate Dehydrogenase •Within the TCA cycle -Regulated by •Availability of substrate -acetyl CoA and oxaloacetate •Cellular energy status (NADH and ATP)- Low energy increases cycle- High energy decreases cycle
Carbohydrates are digested to simple sugars then absorbed into the enterocyte
•Glucose transporter required for transport across cell membrane (polar molecule) •Except for newborn animal (24 - 48 hr), no di-, tri-, or polysaccharides are absorbed. •Transporters -Active transport of glucose and galactose across small intestine via Na-dependent glucose transporter: SGLT1. Uses Na/K ATPase. -Passive transport of glucose by GLUT2 proteins out of epithelial cell into blood vessel = facilitative transport (does not require ATP).
Some background on hormones
•Hormones send signals between tissues -Secreted and carried to another through the blood •Hormones conduct cell to cell communication -Must be secreted from a cell -The target tissue must have a receptor •Hormones regulate -Nutrient metabolism, Growth, & Tissue mobilization •Signal transduction systems in the cell -Relays and amplifies the signal •Synthesis and release of some hormones dependents on -Nutrients available, nutritional status, environment, physiological state etc.
There is reciprocal regulation of synthesis and breakdown of glucose (do not do both at the same time)
•Insulin Decreases and Glucagon Increases Gluconeogenesis •Key Regulated Enzymes - Pyruvate Carboxylase (PC) - Phosphoenolpyruvate Carboxykinase (PEP-CK) These enzyme regulated by -Gene/Protein expression -Allosteric regulation by substrate and products
Insulin binds to the Insulin Receptor activates intracellular signals
•Insulin resistance: Type II diabetes - Failure to respond to insulin because of disruption of insulin signaling 1. No receptor 2. Fails to activate intracellular signal •Type 1 Diabetes (Juvenile): -Pancreas does not produce insulin
Carbohydrates are not an essential nutrient, but provide a majority of the energy in most diets
•Least expensive source of calories Why? Photosynthesis •Animal could not exist without this capture of energy and the oxygen produced. •Starch & cellulose are major E storageforms in plants. Sugars are much lower
Glycolysis takes glucose to pyruvate (6 carbon to two 3-carbon intermediates) - Also called Emden Meyerhoff Pathway)
•Occurs in cytoplasm of every cell in the body •Glucose is the predominant substrate -Also glucose from glycogen, fructose, and other sugars converted to glucose •Not all 10 steps are regulated -Near-equilibrium reactions •Substrate quickly flows through and not regulated -Non-equilibrium reactions •Large free energy changes and regulated •"The dam in the river"
Gluconeogenesis is synthesis of glucose from non-hexose precursors
•Occurs mainly in liver, but also in kidneys Nonruminants - - Rate varies inversely with rate of glucose absorption - Precursors from body tissues/storage Ruminants - - Rate is always relatively high, especially soon after feeding when main precursor is propionate
Hexokinase/Glucokinaseis the first enzyme in glycolysis and is committed and regulated step
•Phosphorylation of Glucose •Committed Step (Every pathway has one!) •Traps Glucose in the cell •Tissue specific isoforms - Differ in Km - Regulated differently (ex. Insulin and glucose inhibition) •Removal of P from glucose only occurs in the Liver and Kidneys (and some in the intestine)!!! Phosphofructose Kinase (PFK) is key regulated step in middle of the pathway
Insulin- Decreases plasma glucose
•Protein hormone from pancreatic β cells (51 AA) •Secreted when blood glucose increases •Short-term regulator (minutes) •Important effects in liver, adipose, and muscle Actions = Anabolic ↑ glucose uptake ↑ glycogen synthesis ↑ lipid synthesis ↑ protein synthesis
Glucagon- Opposite of Insulin
•Protein hormone from the pancreas (α cells) •Secretion ↑ by amino acids, propionate, & butyrate ↓ by glucose, ketones, & fatty acids Actions = mostly catabolic ↓ glucose use by many cells ↑ glycogen breakdown ↓ glycogen synthesis ↑ gluconeogenesis from AA
Summary of the TCA cycle
•The 4-C OAA condenses w/ Acetyl-CoA •Net input = acetyl-CoA •Net output = 2 CO2 + 1 GTP + 4 pairs of electrons
Regulation of cellular glucose uptake is an example of "nutrient partitioning" or directing nutrients to different tissues
•Tissue specific expression of glucose transporter (GLUT) isoforms These are slightly different variations of the same ancestral gene •Differ in: -Regulation (ex. Responsive to insulin) -Biochemical properties •Km and Vmax
Gluconeogenesis requires energy
•Where do we get energy?? -Breaking down glucose would be a futile cycle -Glucogenic AA are going towards making glucose -Fatty acids can be oxidized -Ketogenic AA can be oxidized •These result in ketone formation •Ketones are exported from the liver Type II Diabetes fails to shut off Gluconeogenesis. Results in high Glucose and high Ketones!!! (Sweet smelling breath)