KPE 371: Midterm

Obesity Definition

A progressive chronic disease characterized by abnormal or excessive fat accumulation that impairs health

BMI

Universal definition of overweight and obesity

Obesity (BMI)

\>30 kg/m2

Waist Circumference

Used alongside BMI to assess risk of obesity-related complication

Limitation of BMI

- Does not take body composition into account
- No information on fat distribution
- Hard to interpret across different populations

Direct Methods for Body Composition

MRI & CT
DEXA - Golden Standard

DEXA

Measures % fat distributions and bone density

DEXA Range of Fat %

Risky - Men \> 30%; Women \> 40%

Indirect Methods for Body Composition

Hydrostatic Weighing, BodPod - Lab
Skin Folds, BIA - Field

Energy Balance

Energy in \= Energy out

Energy In

Food/Drinks that contain energy
1 lb \= 3500 calories in excess

Energy Out

- BMR \= Basal Metabolic Rate
- Thermal Effect of Food
- Physical activity

BMR

Amount of energy needed to maintain metabolic processes at rest
- 1 kcal/kg/hr

Calorimetry

Quantification of energy production by the body

Direct Calorimetry

Measuring heat production to determine metabolic rate

Indirect Calorimetry

Measuring oxygen consumption and CO2 produced
- 1 L O2 \= 5 kcal expended

Feedback Processes

Calories in and out are not independent
- Increases appetite & Lowers BMR

Subcutaneous Adipose Tissue

Energy Storage found underneath the skin
- Makes up 80% of total fat
- Stored as TG and released as FFA for energy

Visceral Adipose Tissue

Surrounds vital organs of abdominal cavity
- Makes up 5-20% of total fat
- Associated with an increased risk of disease

Adipose Tissue Composition

- Adipocytes (90%)
- Pre-adipocytes
- Vascular Cells
- EMC
- Immune Cells

The Adipocyte

Cell that store and release fatty acids for energy

Adipocyte Hypertrophy

Increase in size of fat cells that is associated with greater disease risk

Adipocyte Hyperplasia

increase in number of adipocytes

Adipose Tissue Fibrosis

Structure becomes more stuff through more collagen fibers

Net Effect of Obesity

- Loss of adipocyte flexibility as a nutrient storage site
- Increased lipolysis and FA in blood stream
- FFA will find another storage place in the bloodstream

Rate of Resting Metabolism

1 MET \= 3.5 ml/kg/min

Homeostasis

- Maintenance of a relatively constant internal environment
- Disturbances can lead to disease

Glucose Homeostasis

Balance between hepatic glucose production and peripheral glucose uptake and utilization

Insulin

A protein hormone synthesized in the pancreas that regulates blood sugar levels by facilitating the uptake of glucose into tissues
- Primarily ANABOLIC

Glucagon

A hormone secreted by the pancreatic alpha cells that increases blood glucose concentration
- Mobilizes glucose from the liver
- Primarily CATABOLIC

Normal Range of Blood Glucose

4.4 - 5.6 mmol/L

Glucagon's Effect on the Liver

Increase glucose output
- Increase gluconeogenesis
- Increase glycogenolysis
- Decrease glycogenesis

Gluconeogenesis

formation of glucose from non glucose sources

Metabolic Intermediates for Glucose (Gluconeogenesis)

- Lactate
- Alanine & Glutamine
- Glycerol

Glycogenolysis (DRAW)

breakdown of glycogen to glucose

glycogen phosphorylase

Enzyme that cleaves liver glucose from the non-reducing end of a glycogen branch by phosphorylating it
- Turns glycogen to G1-P

Phosphoglucomutase

converts glucose-1-phosphate to glucose-6-phosphate

G6-P Phosphatase

Enzyme found only in the liver that turn G6-P into glucose to be released into the bloodstream

Insulin's Effect on Skeletal Muscle

Increase glucose use and storage
- Glucose uptake
- "Trapping" glucose inside the cell
- Increase glycogenesis and glycolysis

Glucose Uptake

Bringing in glucose from the blood to the muscle
- Glucose requires a transporter

GLUT 4

Important and highly regulated transporter in charge of moving glucose into the sarcolemma

Hexokinase

Enzyme the phosphorylates glucose entering muscle cell and trapping it inside the muscle

Glycogenesis (DRAW)

formation of glycogen from glucose

Glycolysis (DRAW)

A metabolic process that breaks down carbohydrates and sugars through a series of reactions to either pyruvic acid or lactic acid and release energy for the body in the form of ATP

Insulin's Effect on Adipose Tissue

Decrease FFA mobilization and increase glucose uptake
- Decrease lipolysis
- Increase glucose uptake
- Increase TG synthesis (lipogenesis)

Lipolysis

Breakdown of fat

Hormone Sensitive Lipase (HSL)

Enzyme responsible for the breakdown of TG to 3 FAs and glycerol
- Insulin degrades the signal (cAMP) which reduces HSL phosphorylation

Lipogenesis

the metabolic formation of fat

Insulin Effect on the Liver

Decrease glucose output
- Decrease glucose release
- Increase glycogenesis
- Increase glycolysis

Insulin Sensitivity

The degree to which the body's cells respond to insulin

Insulin Resistance

An impaired response of peripheral tissue to respond to insulin
- Same level of insulin concentration doesn't have the same effect

impaired glucose tolerance (IGT)

a state of hyperglycemia that is associated with insulin resistance following ingestion of carbohydrates (also called "glucose intolerance")

Impaired fasting glucose (IFG)

high post-absorptive blood glucose concentration

glycemic control

ability to keep blood glucose levels within normal healthy range

Hyperinsulinemia

Pancreas compensates by increasing insulin production to maintain euglycemia

Prediabetes

impaired fasting glucose or impaired glucose tolerance

Type 2 Diabetes

Clinical condition characterized by high blood glucose concentrations resulting from defects in insulin actions, insulin secretion, or both

fasting plasma glucose (FPG)

Easiest way to test someone's glucose resistance
- Normal < 6 mmol/L
- Pre-diabetic: 6.1 - 7 mmol/L
- Diabetic \> 7 mmol/L

HOMA-IR

Reflects liver insulin sensitivity or Insulin resistance

Fasting Blood Sample

Tells us how well insulin is working to inhibit liver glucose output

Oral Glucose Tolerance Test (OGTT) Ranges

Normal < 7.8 mmol/L
Pre-diabetes: 7.8-11.0
Diabetes \> 11.1

Hyperinsulinemic Euglycemic Clamp

Gold standard measure of insulin resistance
- Acutely raise plasma insulin with insulin infusion
- Infusion of glucose to maintain ~5mmol/L
- High glucose infusion rate \= insulin sensitivity

Glycated Hemoglobin (A1c)

a measure of glucose control that is a result of glucose molecule attaching to hemoglobin for the life of the red blood cell (120 days)
Normal < 6 %
Pre-Diabetes: 6.0 - 6.4%
Diabetes \> 6.5%

Adipose Tissue Expandability

Once adipose tissue expansion limit is reached, lipid can no longer be stored appropriately
- If lipid is not stored in adipose tissue, it finds somewhere else

Glycerol measures

lipolysis

Lipodystrophy

Inability to store fat as triglyceride in subcutaneous fat

Inflammation Hypothesis

increase of secretion of adipokines from adipose tissue
- FFA release activates macrophages
- Causes the release of pro-inflammatory cytokines that cause insulin resistance

Tumour necrosis factor (TNF-a)

Increases secretion of other pro-inflammatory cytokines
- Impairs insulin signaling in adipocyte
- Increases HSL and reduces GLUT4

Interleukin-6 (IL-6)

Increases lipolysis via increase of HSL

Adipokine Hypothesis

Adipose tissue secretes more adipokines that cause insulin resistance and less that promote insulin sensitivity

Leptin

- Produced in proportion to amount of fat mass
- Role is to decrease hunger and suppress food intake
- Promotes glucose uptake in muscle and decreases lipid accumulation in liver
- High production can lead to leptin resistance

Adiponectin

- Production decreases with obesity
- Role is to decrease hepatic glucose output, macrophage infiltration, increase muscle glucose uptake

Liver Insulin Resistance (DRAW)

Fatty-Acyl CoA releases lipid intermediates (ceramides, DAG) which inhibit IRS-1 signaling, resulting in lower glycogen synthesis

De Novo Lipogenesis (DNL)

The process by which fatty acids are synthesized from other compounds (e.g., glucose) within the liver
- Causes more insulin resistance

Skeletal Muscle Insulin Resistance (DRAW)

- IRS-1 is blunted which is the first step in the signaling pathway
- Limited GLUT4 translocation

Athlete's Paradox

Athletes show an elevated level of IMTG, similar to T2D but have different insulin sensitivity

Lipotoxicity

Oversupply of FFA leads to accumulation of lipid intermediates (DAG, Ceramides) which impair insulin signaling cascade

Glucose-Fatty Acid Cycle (Randle Cycle)

- Explanation for how availability of fat regulates CHO use
- More to do about energy availability than impairing the cascade

Phosphocreatine System (PCr) (DRAW)

Uses Creatine Kinase to break down PCr and ADP to ATP and Cr

Glycolytic System (DRAW)

Aerobic Energy System (DRAW)

The system responsible for most energy production in the body through the Krebs cycle and the electron transport system; takes place in the mitochondria and requires glucose and oxygen; also known as aerobic respiration.

fatty acid oxidation (DRAW)

the metabolic breakdown of fatty acids to acetyl CoA

beta oxidation of fatty acids (DRAW)

Fatty Acyl CoA enters mitochondria through CPT1
- All substrates are used for the rest of the aerobic processes

Allosteric Regulation

The binding of a regulatory molecule to a protein at one site that affects the function of the protein at a different site.

Covalent Regulation

regulatory mechanism in which changes in an enzyme's activity are brought about by the covalent bonding of a specific chemical group to a site on the enzyme molecule; usually involves bonding of a phosphate group

Creatine Kinase

Regulated solely by substrate and product concentration (PCr)

Phosphofructokinase (PFK)

a key rate-limiting enzyme of the anaerobic glycolytic energy system

Allosteric Regulation of PFK

- At rest, ATP is available and inhibits glycolysis
- ADP, Pi, AMP reduce ATP binding which increases PFK activity
- H+, citrate increase ATP binding which reduces PFK activity

PHOS b

Unphosphorylated form of glycogen phosphorylase (inactive)

PHOS a

Active or Phosphorylated form of glycogen phosphorylase

PHOS Kinase

Enzyme in charge of turning "on" PHOS b to PHOS a

PHOS Phosphatase

Enzyme in charge of turning "off" PHOS a to PHOS b

Allosteric Control of PHOS Kinase

Calcium, EPI, ADP, AMP are regulatory signals that control of PHOS Kinase signal energy deficiency

Pyruvate Dehydrogenase (PDH)

converts pyruvate to acetyl-CoA

PDH a

Active or Phosphorylated form of PDH

PDH b

Inactive or Dephosphorylated form of PDH

PDH Kinase

Enzyme in charge of turning "off" PDH a to PDH b

Regulation of PDH Kinase

Acetyl CoA, NADH, ATP all signal energy availability to PDH Kinase

PDH Phosphatase

Enzyme in charge of turning "on" PDH b to PDH a

Regulation of PDH phosphatase

Calcium, Pyruvate, NAD, ADP, AMP all signal energy deficiency and turn on PDH phosphatase