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81 Cards in this Set
- Front
- Back
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Disease states with energy imbalance
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- obesity
- anorexia - cachexia |
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Obesity arises...
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Commonly accepted: if the input of energy from food exceeds the output of energy
But, childhood demands energy input exceeds output |
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Normal growth requires
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+ calorie balance
- causes of obesityinput of energy and organic matter that aexceeds output may not lead to obesity |
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Evolution favors...
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- physiologica mechanisms with exess input combined with mechanisms that discard the excess
- accommodates input of food with variable compositions and times of inputs not matched to day to day energy needs - accomodates continuous ingestion of excess of substances to input minimum amts of susbtances scarce in diet |
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Energy content of food
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1. Protein
2. Carbohydrate 3. Fat Humans store energy in same forms but not same ratio as in food |
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Obesity arises from
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- excessive accumulation of fat --> fattty acids esterified to gylcerol to form mono, di and triglycerides
- obesity is not the accumulation of calories -Obesity results form an inc in the relative, not total, amount of adipose tissue mass - If the relative amt of fat the body burns is less than the relative amount in the food an increase in relative body fat content must result |
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Adipocytes and adipose tissue
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cells specialized to store triglycerides
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Carbohydrates vs. Fatty acids
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Carbohydrates C:H:O ratio 1:2:1, every carbon is partially oxidized
Fatty acids C:H:O ratio 1:2:0.13 only 1/16 carbon is partially oxidized cabons in carbohydrates are more oxidized than carbons in fat full combustion of carbohdrate req less input of oxygen |
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Body release energy from food by
1. RQ ratio 2. FQ ratio |
combusting it to CO2 and H2O
- amount of CO2 produced/ amount of O2 consumed 1. respiratory quotient determined for living organisms 2. food quotient- determined for food "burned" ex vivio constant body composition req FQ=RQ For Fat, RQ(and FQ)= 0.7 for carbohydrate RQ(and FQ)=1 protein RQ=0.8 ex vivo overestimates carbohydrate content bc some carbs are not digested or absorbed |
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Amino acids and proteins
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- AA used to build proteins and not combused for energy
- excess ingestion of AA for protein syn the excess AA are burned and produce energy - some AA stored as protein in muscle and muscle thus becomes energy storage depot |
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Measuring AA
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- prior to combusion nitrogen is removed from AA by urea cycle --> urea in urine
- measure urea output in urine can be used to estimate the contribution of AA to combusion and improve the use of RQ to estimate the ratio of fat and carbohydrate combustion in vivio |
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RQ> FQ
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- leads to obesity
- indicates fat content of ingested food exceeded the fat content of metabolized food - even if person is in calorie balance R!>FQ indicates relative adipose tissue mass is increasing, body composition is changing and obesity may result |
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Fat is efficient form of energy storage
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- carbons in fat have more potential energy
- carbohydrates are partial oxidized, the oxygen in carbohydrate contributes to its mass - both carbohydrate (glycogen) and AA (protein) are hydrophilic and stored with water molec - fat is hydrophobic --> lipid droplets --> weight and V more efficient |
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1. Absorptive state
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- the few hours during and after a meal
- a substantial amount of metabolites are absorbed form the gut and are either burned or stored |
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2. Post absorptive state
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- period following the absorptive state when meaningful input form the gut ceases and metabolites flow from storage sites to utilization sites
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3. Starvation
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- the adaptation that results if a prolonged period (> 24 hours) ensues with no food input
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Absorptive state
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1. Carbohydrate, largelly glucose and fructose, as a major source of energy for all cells
- combustion of FA is reduced 2. Net synthesis of protein from amino acids - depleted depots of protein are restored 3. Net storage of glycogen, particularly in the liver - func of liver is to maintain blood glucose at a level sufficient to supply glucose to nervous tissue and erythrocytes - store glucose as glycogen during absorptive state for release during post absorptive 4. Net storage of TG particularly in adipose tissue 5. Conversion of AA and carbohydrates to fatty acids |
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Hydrolysis of TG in circulating chylomicrons and VLDL
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- inc concentration of FA in perfustate of adipose tissue
- facilitate entry of FA into adipocytes - hydrolysis of circulating TG by capillary lipoprotein lipases in adipose tissue - adipocytes do not use glycerol produced by adipose tissue capilary lipases |
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Glycerol-3-P
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- becomes the glycerol backbone in syn of TG
- Adipocytes lack glycerol kinase - adipocytes use carbohydrates (extracellular glucose or intracellular glycogen) source of Glycerol-3-P for syn of triglycerides |
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Glycerol kinase
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-uses ATP to phosphorylate glycerol
- found in liver and kideny |
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AA, carbohydrates --> FA
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- via transamination of the urea cycle, carbons of AA--> glycolysis
- glycolysis --> acetyl CoA--> FA--> stored as TG - anaerobic glycolysis- changes composition of organsism |
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Anerobic glycolysis
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- changes composition of the organisms by Inc # of reduced carbon atoms which can flow into fat
- process is irreverisble - can inc the relative fat content of the organism |
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The postabsorptive state
Step 1 |
-Utilization of FA as a major energy source
-spared combustion of glucose - FA and ketoacids become major source of energy (except nerous tissue and erythrocytes use glucose) - inc circulating level of FA directly on muscle to dec glucose utilization |
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The postabsorptive state
Step 2 |
- net release of FA from adipose tissue
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The post absoprtive state
Step 3 |
- maintanance of blood glucose levels via net hepatic glucose production
-Glucose-6- phosphatase in liver allows Glucose -4- P (from gluconeogenesis or glycogenolysis ) to be convereted to glucose and release - tissuess that lakc glucose 6- phosphatase, retain the glucose derived from glycogenolysis for utilization within the cell -- comblete combustion to H2O and CO2 -- anaerobic conversion to lactate leaves tissue and enters hepatic gluconeogenesis |
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The postabsorptive state
Step 4 |
- net protein degradation with hepatic conversion of AA to glucose
- nitrogen must enter the urea cycle and be excreted as urea by the kidney |
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Nervous systems needs glucose during post absorptive state gets glucose from..
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liver from
1. glycogenolysis 2. gluconeogenesis |
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Starvation period
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- longest period without food --> overnight fast
- morning--> liver glycogen stores are depleted and liver uses gluconeogenesis to maintain blood glucose - liver uses lactate or AA from muscle |
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Total amt of glycogen (liver and muscle) and protein (muscle)
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- maintain body functions for only a few days
-avoid compromised muscle function --> heavy reliance on breakdown of muscle protein, nervous tissue --> utilize ketoacids derived from fat as metabolic fuel |
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Storing and utlizing energy: Neuroendocrine control
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- CNS --> organs producing heat doing work
- Organs storing energy: TG, carbohydrate, protein - Endocrine system: thyroid, adrenal, pancreas |
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Insulin (absorptive state)
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- insulin regulate metabolite flows in the absorptive state
- insulin promotes storage of energy and growth - insulin --> anabolic hormone 1. promotes burning of carbohydrate 2. stroage of fat and protein 3. Reduction in circulating levels of glucose, AA, FA - insulin changes not just the circulating levels of metabolites but the storage and utilization of metabolites |
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Insulin (absorptive state)
1. Promotes glucose uptake into the muscle |
- glucose --> muscle, gets phosphorylated
- muscles lack glucose 6- phosphatase --> cannot leave stored as glycogen or catabolized to lactate --> release as acetyl coA --> CO2 and H20 - insulin promotes muscle combustion of CHO and reduces utilization of fat |
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Insulin (absorptive state)
2. Promotes glycogen accumulation |
- insulin promotes dephosphorylation and activation of glycogen synthase and deactivation of phosphorylase --> coordinated control --> glycogen accumulation
In muscle and fat |
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Insulin (absorptive state)
3. Promotes AA uptake and protein accumulation particularly in muscle |
- not limited to promotion of AA transport
- insulin alters cell functions to retard protein breakdown - protein accumulation --> reservoir of AA for later conversion to glucose |
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Insulin (absorptive state)
4.Promotes TG storage in adipose tissue |
- promote entry of glucose into adipocytes, insulin supply cell with glycerol-3-P the required precursor of TG formation
- insulin promotes dephosphorylation and deactivation of hormone sensitive lipase -hyperinsulinemia --> proposed cause of obesity |
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Regulation of insulin secretion
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- inc in circulating glucose and AA --> stimuli of insulin secretion
- insulin promotes uptake of glucose/ AA --> lowers circulating level --> NEGATIVE feedback loop - |
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Fight or flight response
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- increase hepatic glucose output in response to sudden change
- response ensures a supply of glucose to nervous tissue adn erythrocytes |
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CNS act via
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paraympathetic vagal neurons to promote insulin release
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increatins
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- released from the gut during digestion
- inc incretins distinguish a glucose rise due to digestion from a rise due to hepatic glucose output |
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GLP-1 glucagon- like peptide 1
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- lowers blood glucose by increasing insulin release
- suppresses release of glucagon - reduces rate of gastric emptying - ex. byetta gLP-1 analog |
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Inhibiting insulin secretion
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- activation of sympathetic nervous systems --> fight or flight response --> inhbits insulin release
- pancreatic B cells (site of insulin synthesis and release) --> two sympathetic signals 1. norepinephrine (sympathetic nervous system) 2. epinephrine (adrenal medula --> act alpha adrenergic receptors on Beta cells --> also have B adrenergic recptors --> activation of receptors inc cAMP and promotes insulin release - ratio of alpha to beta --> alpha effects to dominate from epinephrine |
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Ratio of Alpha to beta receptors
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cause alpha effects to dominate responses from epinephrine
- pure Beta adrenergic agonist (isoproterenol) promotes insulin release |
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Somatostatin
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- pacreatic produced
- inhibits insulin release |
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Destruction of pancreatic B cells -->
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- insulin deficiency and dramatic loss of adipose and tissue mass
- admin insulin --> restores adipose tissue mass |
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Human Type 1 diabetics
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-lack insulin
- loose adipose mass if insulin therapy is absent |
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Hyperinsulinemia
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- characterizes obese humans
- hypothesis--> hyperinsuleinemia --> causes obesity |
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Insulin --> to promote accumulation of adipose tissue mass
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- needs to be pulsatile
- constant infusion of insulin causes desensitizationa nd no inc in adipose mass - normal insulin secretion is pulsatile, pulses are greater in obese - insulin resistance--> when hyperinsulinemia , obese persons are not hypoglycemic |
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Amylin
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- found in amyloid deposits of pancrease of pts with type 2 diabetes
-amylin inhibited insulin- stimulated glucose uptake and glycogen deposition in muscles with little effect on insulin action on adipocytes - |
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Excercise
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-makes muscle uptake of glucose more insulin sensitive
- excercise also shifts fuel utilization at rest toward fat oxidation - excercise --> loss of adipose mass not by calorie consuption but also from effects on neuroendocrine regulation in part by increasing insulin action on muscle and by increasing muscle combustion of FA |
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"glycemic index"
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-area under the glycemic response curve compared to the same amt of a standard food such as glucose
- large pulse of glucose --> produce pulse of insulin-->might favor accumulation of adipose tissue mass and an ensuing hypoglycemia that might lead to more eating |
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nsulin regulation of glucagon release
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- insulin is made by the beta cells in the Islands of Langerhansof pancreas
- Islands are alpha cells that produce glucagon--> pancreatic endocrine hormone that opposes many actions of insulin--> glucagon spares glucose utilization and promotes lipolysis - insulin dec release of glucagon - insulin is release in the islets near cells producing glucagon -> action of insulin is paracrine ---> insulin diabetics receive does not have same paracrine actions |
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Glucagon
1. |
-promotes release of Fatty acids from adipose tissue
-inc cAMP and promotes phosphrylation of hormone sensitive lipases --> breaks down TG --> FA -glucose entry into adipocytes is impaired and FA are released, not reesterified to TG. Resulting flow of FA --> muscle dec combusion of glucose - |
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Glucagon
2. |
-promotes release of glucsoe from liver
-glucagon inc phosphorylation of glycogen synthase and phosphorylase --> promote glycogenolysis and glucose release - flow of AA and pyruvate/lactate to glucsoe via gluconeogenesis is enhanced |
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Epinephrine
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3. Acts on muscle to dec insulin action, and promote glycogenolysis and lactate efflux
4. Promotes glucagon and inhbits insulin release 5. PRomotes blood flow through adipose tissue, lipolysis and fatty acid efflux |
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A lack of glucagon or epinephrine could lead to ...
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hypoglycemia, detected by gluco-receptors in the CNS and the urge to eat
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1. Hypoglycemia is due to..
2. Hyperinsulinemia |
1. failure to metabolize FA from adipose tissue
2. might promote fat deposition by diminishing the release of fat from adpiose tissue - so might dec amts of glucagon and epinephrine |
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CNS lesions
1. Lesions to the lateral hypthalamus (LH) 2. Lesions to the ventromedial hypothalamus (VMH) |
- CNS food intake (sensation of gut distension) and adipose mass (leptin)
- regulate metabolite flows, food input and thermogenesis 1. cause anorexia (hypophagia) and adipose tissue wasting 2. cause voracious overeating (hyperphagia) and obesity |
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Experiment:
VMH- lesioned animals are pair fed with controls |
- lesioned animals still gain more weight and adipose mass than the controls
- demonstrates that overeating alone is not the cause of obesity - VMH lesioned animals are less thermogenic and less active. - if insulin secreting pancreatic islets are chemically destroyed (drug streptozotocin) and replaced with transplanted islets that then lack the vagal connection to the CNS--> VMH lesions are less effective in causing obesity ---> CNS controls adipose tissue mass at least in part via vagal control of pancreatic insulin secretion |
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CNS can be altered by
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-trauma, drugs, infectious disease genetics--> may cause obesity
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Leptin
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- adipose tissue produces an endocrine like factor indicating its mass that would regulate metabolism via a regulatory loop involving the CNS
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Mice study with leptin
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- inbred strain of mice with a recessive mutation in ob gene
- homozygous for the ob mutation (ob/ob) --> obese --> lack ob gene product |
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If gave leptin to ob/ob mice -->
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- eat less, inc body temp, lose relative adipose tissue mass
- does not occur in control mice |
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db/db mouse
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- high circulating levels of leptin
- fail to respond to administered recombinant leptin -cause of phenotypes --> mutation leading to dysfunctional CNS leptin receptor |
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gut is a neuroendocrine organ
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- stomach and insestine fill with food --> distension and the composition of the contents cause neural and endocrine signals to be sent to the brain and other organs which regulate eating behavior and the disposition of the digested food
ex. GLP-1 |
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GLP
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- increase the release of insulin in response to an increase in blood glucose
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neuroendocrine singals form the gut arise from..
Gustducin |
G protein coupled receptors
- GPCR in mouth coupled to G protein (gustducin)--> senesation of taste - taste receptors recognize sweet substances and gustductin in intestinal cells regulate release of GLP-1 form teh gut |
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GPCR in gut recognize short chain fatty acids (SCHFAs)
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- signal presences of SCFA in the gut
- different bacteria in gut metabolize food to diff compositions that interact with these receptors - bacteria in gut participate in diguestion and produce signals to indicate composition contents in gut |
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Hormone in the gut
Ghrelin |
- 20AA peptide hormone release from stomach
- unique O-linked octanoyl side group critical for action to CNS receptor -octanoyl group from food in the stomach and is coupled to the peptide by gastic enzyme (GOAT) ghrelin O-acyl transferase - ghrelin is a signal indicating composition of the contents of the stomach |
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Thermogenesis
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- generation of heat
- required to maintain body temp in cold enviornments - if energy absorbed from food exceeds the energy expended in accomplished work --> achieve energy and organic matter balance, energy must be lost as heat form oxidation of organic matter with the same composition as the food |
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NEAT- Nonexercise activity thermogenesis
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- imperfect coupling of energy production to work produces heat
- useless activity like fidgeting, regulated mechanism to dispose of energy - inc in NEAT --> major mechanism used by individuals to dispose of energy from overeating |
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Thermogenesis from oxidation uncoupled from activity
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- slight chagnes in the permeablity of cell membranes to Na/K would allow inc activity of Na/K ATPase to consume energy
- uncoupling proteins --> mech to throw off excess energy as heat |
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brown adipose tissue (BAT), an uncoupling protein (UCP)
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-disspiates the hydrogen ion electrochemical potential gradient in mitochondria by uncoupling oxidation fromt he generation of ATP
- oxidation produces heat - uncoupling protein also found in white fat, kidney, muscle |
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UCP1 uncoupling protein 1
UCP2 UCP3 |
- UCP1 first discovered isofrom found in BAT
- UCP3 is isoform in muscle and may be involved in generating much heat in humans |
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BAT in infants
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- sufficient quantity and activity towards generating an amt of heat relevant to maintaining body temp and throwing off excess energy input
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BAT in adults
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- hyptothesis that BAT is relevant for heat production and was regulation of energy output in adults
- stimulating BAT thermogenesis in adults have therapeutic potential |
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mice B- adrenergic receptors experiment knock out all three known B adrenergic receptors
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- role in thermogeneiss arising in reposne to cold exposure or from high fat diet
- knocking out 3 receptors --> modest inc in weight on normal chow, inc on high fat chow - indicate sympathetic innervation and CNS play key role in adapting to high fat diet - if system dysfunctional in humans--> reducing fat in diet would help achieve energy and organic matter balance --> blunt a thermogenic response to cold exposure |
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in mice knocking out UCP's
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- cold intolerance but not obesity
- transgenic mouse --> promoter region of UCP1 was coupled to DNA encoding for diphtheria toxina --> led to ablation of BAT - early mice--> no overt pathology - several weeks --> mice cold intolernat, obese, and hyperphagic |
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Lack of BAT
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- eliminates mechanism to burn off excess energy in ingested food elading to obesity
- does not explain hyperphagia or why UCP1 knock out mice are cold intolerant but not obeses - alternative hypothesis --> BAT sends endocrine signals to CNS, abs of signals --> hyperphagia (like lack of leptin) - muscle may also produce endocrine singals |
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1. Gastric banding
2. Rous-en Y gastic bypass |
1. approach to reduce meal size
- leads to improvement of Type 2 diabetes over months - weight loss 2. cause malabsorption -improved glucose tolerance within days - weight loss - altering role of GI tract in neuroendocrine regulation of metabolism |
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Gut microbiome and energy and organic matter balance
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- gut microbiome (amt, type, distribution of bacteria in gut) influences digestion and absorption of food also func of the gut as an organ participating in neuro-endocrine regualtion of energy and organic matter balance
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Agiogenesis, adipocyte progenitor cells, and sites of adipose tissue expansion
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- expanding vasculature req to support expanding adipose tissue
- Question: - inc number of locally dividing adipocytes create a demand for an expanding vasculature or whether a combination of bone marrow derived adipocyte precursors interact with the adipose tissue vasculature to cause expansion of adipose tissue |
