Metabolism and Energy Balance

• Unit 7 focuses on metabolism and energy balance
• Topics include a metabolic primer, regulation of eating, and the modern problem of obesity
• Also explores the roles of insulin, endocrine responses to hypoglycemia, and calcium homeostasis

Regulation of Metabolism

• It refers to life-sustaining chemical conversions within living organism's cells
• Translation of energy substrates is biased towards storage/anabolism (building) or breakdown/catabolism (destroying)
• The endocrine system is primary in regulation, specifically products of the endocrine pancreas via the insulin/glucagon ratio
• The neural system regulates food intake, with the endocrine pancreas also innervated autonomically

Energy Usage and Storage

• Ingested biomolecules are either metabolized for fuel, built into tissues, or stored as glycogen/fat
• Metabolism has two states: fed/absorptive (anabolic) and fasted/postabsorptive (catabolic)
• There are immediate nutrient pools available from circulating glucose, fatty acids, and amino acids in the plasma

Enzyme Control

• Metabolic direction is under enzyme control
• Enzymes in the fed-state, influenced by insulin, increase forward reaction activity and inhibit glycogen breakdown
• Enzymes in the fasted-state, influenced by glucagon, are more active in breaking down glycogen and inhibiting glycogen synthesis

Nutrient Interconversions

• Carbohydrates, fats, and proteins can be interconverted
• In the fasted state: Glycogen in the liver breaks down into glucose and is exported as free glucose
• Glycogen in muscles cannot be exported as free glucose and is either used within the muscle or exported as pyruvate or lactate to the liver for gluconeogenesis
• Triglycerides in adipose tissue export glycerol to the liver for gluconeogenesis and export fatty acids for beta-oxidation -The liver can produce ketone bodies from fatty acids
• Muscle proteins break down into amino acids, used within muscles, or exported to the liver for gluconeogenesis

Fasted-State Metabolism

• Metabolites during the fasted state are derived from the break down of glycogen to be used as glucose
• Triglycerides breakdown into FFAs and glycerol that enter the blood to be used as energy
• Muscles use fatty acids and also breakdown their proteins into amino acids that enter the blood
• The brain can only use glucose and ketones for energy

Ketogenesis

• Ketone bodies form when lipolysis occurs faster than acetyl CoA can be used in the TCA cycle
• Ketones can enter the blood and act as an energy substrate for the brain during starvation
• Ketones are typically generated by low-carb, high-fat/protein diets
• Ketogenesis can be dangerous, producing strong metabolic acids, which become ketoacidosis

Homeostatic vs. Non-Homeostatic Eating

• Homeostatic eating occurs when energy fuels are depleted and is metabolically driven
• Non-homeostatic eating occurs in the absence of hunger, despite large fat reserves, and can involve cognitive, reward, and emotional factors similar to addiction

Influences on Eating

• Environment and lifestyle factors, cognitive and emotional brain centers, and internal milieu influence energy intake/output
• Individual predisposition is influenced by genetics, epigenetics, imprinted genes, and early life events
• Homeostatic eating is regulated by 'hunger'/'feeding' and 'satiety' centers monitored by glucose levels in the hypothalamus
• Fat stores modulate eating behavior using hormones like leptin synthesized in white adipose tissue

Leptin and the ob/ob Mouse

• Leptin was discovered through studies of the ob/ob mouse, which has a spontaneous mutation leading to obesity and voracious eating
• The 'ob' gene was identified/sequenced and revealed a mutation in the ob/ob mouse which prevented the production of leptin needed
• Another mutation was discovered with a similar phenotype, which affected the leptin receptor known as db/db mouse

Gut Signals Regulating Eating

• Ghrelin from empty stomach cells increases appetite
• Stomach stretch and acid stimulate decreased appetite
• CCK response to fat/protein, and glucose also decrease appetite in the upper small intestine
• Peptide YY (PYY) and GLP-1 inhibit neuropeptide Y release, which decreases appetite in the lower small intestine

Peptides That Control eating

• Neuropeptide Y, other neuropeptides, and hormones combine to up or down stream hypothalamic feeding center
• This stimulates food intake which produces more leptin
• Ultimately those factors send inhibitory signals along the feedback loop
• Many hormones, neuropeptides, and products of adipocytes interact to influence appetite

Obesity

• High appetite is due to modern environments stimulating higher brain regions, ease of food, and genetics
• The body defends the lower limits of adiposity
• Leptin resistance causes summer-building behavior of "overeating," despite being in "perpetual summer"

Leptin Deficiencies

• Leptin deficiencies are rare in humans
• The 1st case was found in 2 cousins from Pakistan who could not produce the protein
• Leptin treatment has restored the body weight of those with Lep gene deficiencies

Insulin Actions

• Insulin secretion increases in the fed/absorptive state which allows:
  • More glucose oxidation
  • More glycogen synthesis
  • More fat and protein synthesis

Insulin:Glucagon Ratio

• Insulin increase glycogenesis and glucagon increases glycogenolysis
• Insulin increases lipogenesis

Islets of Langerhans

• Endocrine pancreas products get out via blood vessels

Insulin Expression

• Distension of GI tract affects Mechanoreceptors and Stretch receptors
• Gut lumen Carbs affect Chemoreceptors in the small intestine
• All factors combine to stimulate the CNS and Parasymp that leads to B cell activation

Features of Pancreatic Beta Cells:

• GLUT2 transporters move glucose using facilitated diffusion
• K+ leak channels are open until inhibited by the presence of ATP
• Voltage-gated Ca2+ channels open when there is sufficient depolarization

Insulin Release

• ↑ plasma glucose (> 100 mg/dL),↑ plasma AAs
• ↑ GLP-1, ↑ GIP
• ↑ parasympathetic

Insulin Action Targets

• Primary targets are striated muscle, adipose (using Glut4 transporter) and on the liver
• Glucose transport into Glut4 expressing target cells can lead to:
  • Increased glucose metabolism
  • Increased glycogenesis
  • Increase fat synthesis and protein synthesis

Insulin Regulation

• Extracellular Insulin binds to tyrosine kinase receptor which phosphorylates insulin-receptor substrates
• Second-messenger pathways later protein synthesis, while membrane transport is modified
• Metabolism is also changed once its cell metabolism is impacted, GLUT4 accepts more glucose into muscles and adipose tissue

Insulin Effects in Hepatocytes

• In fasted state, hepatocytes make glucose and export it via GLUT2 transporters
• In fed state, gradient favors glucose import, which is used and stored in glycogen stores

Diabetes Mellitus

• Characterized by elevated blood glucose (hyperglycemia)
• Results from:
• Inadequate insulin secretion
• Abnormal target cell responsiveness

Acute Pathophysiology of Type 1 Diabetes Mellitus

• Fats increase and break down while fats use for ATP go up
• Not enough glucose is not taken up for ATP production which can overload the kidneys
• Protein breakdown occurs and creates tissue loss

Type 2 Diabetes

• Accounts for ~90% of diabetes cases
• There is insulin resistance with delayed response to an oral challenge
• It is linked to low, normal, or high secretion of insulin
• Acute symptoms are not as severe, but there are risks such as atherosclerosis, hypertension, and metabolic Syndrome

Glucagon

• Glucagon antagonizes the effects of insulin and is produced by alpha cells
• Trigger for its release is low blood glucose
• Is used over overnight fasts to prevent hypoglycemia, 75% from glucose by 25% from non-carb sources

The Adrenal Gland

• Adrenal steroids is located at the level of the kidneys and include:
  • Mineralo corticoid for the absorption of Na+ by aldosterone
  • Gluco corticoid by cortisol, corticosterone -Sex Steroids produced by weak' androgens and testosterone
• The products are regulated at the level of the hypothalamus-Pituitary Adrenal axis that increases the blood level

Hormones and Glucose

• Liver
• Lactate pyruvate
• Fatty acids in the muscle adipose combine to create Ketone molecules
• Pancreatic factors play a role in glucose homeostasis with increased uptake or reduced levels of the hormones

Steroidogenic Pathway

• A series of chemical reactions that transforms cholesterol into various steroid hormones
• Side chains removed from:
  • Progesterone and Aldosterone
  • Androstenedione and Testosterone
• It releases:
  • Estrone and Estradiol

Stress & Cortisol

• Hormonal production is regulated by Hypothalamic-Pituitary-Adrenal axis in response to low levels of glucose
• Causes a feedback response to release cortisol at the adrenal cortex when needed for increasing levels
• In turn it is regulated by:
  • Immune System and Suppression
  • Gluconeogenesis
• Protein Catabolism
• Lipolysis
• Glucocorticoids are secreted by all nucleated in response to stress to help the body

Glucocorticoid Targets

• Glucocorticoids increase enzyme expression
• Prevent hypoglycemia
• Have a permissive effect with Epi
• Suppress the immune response
• Overall it is related to the metabolism of fats, protiens, and carbs

Selye and Stress

• Selye developed the concept that stressors are always generic responses
  • Adrenal Hypertrophy
  • Atrophy Thymus, Lymph
  • GI Ulcers

Epinephrine and the Fight or Flight

• Norepinephrine is produced in nerves while Epinephrine is produced in hormones
• Both hormones and nerves signal for the mobilization of energy
• Lipolysis and increase glycogenolysis, and increase or decrease in glucose
• Effects are similar to glucagon

Thyroid Gland

• Secreting thyroid hormones decrease the amount of calcium in the blood, while parathyroid increases
• Thyroid stimulates hormone secretion
  • In turn thyroid hormones aid the metabolic actions in bone, heart, and muscle

Thyroid Hormones

• Created from amino acid derivatives that dissolve in fact
• There are T4 and T3 secretions which come from iodine in the body T3 - most active form where it is regulated in the cells

Thyroid Action

• Essential for normal growth, and especially in normal babies
• Is not essential in adults- has impacts on substrates for oxidative metabolism
• Increases basal metabolic rate
• Interacts with normal hormones to modulate carbohydrates, protiens, and lipids

Growth Hormones

• Regulated and controlled growth through:
  • Growth is direct using cell receptors by insulin uptake
  • Is mediated by target cells, and liver or other issues
• GH both inhibits and promotes certain things
• Liver and other issues promotes in a certain zone
• Prevent hypoglycemia where tissue and cartilage growth has to occur together

Actions of Growth Hormone

• Carbo uptake leads to increase in plasmic hormones
• In both aspects and anabolically

Growth Hormome Pathologies

(Decreased Secretion)

• Deficiency due to hyposecretion which causes Dwarfism [ Excess GHR]
• GHR excess where it may be too short, or it causes acromeagly

Regulation of Calcium

• Has extracellular and intracellular functions
  • Hormone synthesis
  • Smooth tissue release
• Largest bone reservoir
• Remodeled to maintain equilibrium in most matrixes through the use of ostoeblats which lay down Ca, CL, or PH
• Ostooclasts secrete in the kidney where there is acid and breakdown
• It is produced via:
  • Paracelluler and Transcellular Routes, where the hormone is regulated

###Calcium Transport

• Hormone controlled reabsorption is at the Distal Nephron
  • It increase Ca by Gut Activity
  • Assisted in Bone Resorption

Parathyroid

• PTH is released in response to Low Plasma
  • Kidney= increasing calcium reabsorption
  • Bone= Increases Ostreoclast and creates reabsorption Small Intestines = Increase Calcium

Hormones

• D Vitamins: Come from diet and the sun

Homeostasis of Calcium

• Calcium is an important factor in hormones that regulate hormone secretions throughout the body
• Ca also regulates calcium itself by responding to low and heaty levels
• PTHs help release absorption from the stomach, reabsorption from nephron, and resorption by bone

Bone Remodeling

Paracrine signaling driven by Vitamin3 helps increase the relationship and activity of bone.