Feeding & Energy Balance

What does the 1st law of thermodynamics state in relation to the body’s energy?  

 The body’s energy inputs must balance the sum of the energy outputs. Energy can neither be created nor destroyed.

How is basal metabolic rate (BMR) defined and what factors influence it?  

What are the determinants of metabolic energy expenditure?  

BMR = minimum rate of energy production to sustain vital functions in waking state.  

Factors: age, gender, weight, hormonal status.

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• Resting metabolism (60–75%): BMR, sleeping metabolism, arousal metabolism

• Physical activity (15–30%): at work, at home, sports and recreation

• Feeding thermogenesis (10%)

• Other factors: thyroid hormone, growth hormone, androgens, climate, aging, sleep, fever, stress, starvation

What are the two components of feeding energy expenditure?  

• Obligatory thermogenesis: energy requiring processes related to assimilating food (motility, secretion, digestion, absorption)

• Facultative thermogenesis: related to activation of endocrine (insulin/glucagon) and autonomic nervous systems and their stimulating effect on metabolic substrate mobilization (glycogenolysis and lipolysis), storage (glycogenesis and lipogenesis) or processing (gluconeogenesis).  

ermic effect of food is maximal 1 hr postprandial.

What are the hunger and satiety centers and how do they function?  

• Hunger center: located in lateral hypothalamic area; stimulation elicits voracious appetite even after ingestion of adequate food.

• Satiety center: located in ventromedial nucleus (VMN); stimulation elicits sensations of satiety even in the presence of food.  

od intake is regulated by hypothalamic centers.

What conclusions were drawn from parabiosis experiments involving Ob and Db mice?  

What roles do leptin and leptin receptors play in Ob and Db mice?  

• Db mouse makes an excess of a blood borne factor that cures Ob.

• Db mouse lacks receptor for this factor.

• Absence of the receptor in the Db mouse removes negative feedback leading to high levels of the blood borne factor.

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• Wildtype mouse has leptin, and this helps the Ob mouse feel “satisfied” and not overeat.

• The Db mouse lacks the leptin receptor, therefore overeats and overproduces leptin. Leptin enters the Wt mouse and its effect on satiety causes the Wt mouse to starve.

• Since the Db mouse makes plenty of leptin, its overproduction helps cure the Ob mouse.

What circulating hormones and signals affect the satiety and hunger centers?  

• Leptin: Adipocytes are primary producers of leptin. Leptin levels rise in proportion to the mass of adipose tissue. Acute changes in food intake or fasting do not appear to appreciably affect leptin levels. Leptin provides long-term feedback on body status.

• Insulin: Levels change dramatically daily in response to food intake. Insulin provides short-term feedback on body status.

What are the anorexigenic effects of leptin?  

• Stimulation of leptin receptors decreases fat storage.

• Decreased production in the hypothalamus of appetite stimulators, such as NPY and AGRP.

• Activation of POMC neurons, causing release of α-MSH and activation of melanocortin receptors.

• Increased sympathetic nerve activity, which increases metabolic rate and energy expenditure.

• Decreased insulin secretion by pancreatic beta cells, which decreases energy storage.

• Adipose tissue uses leptin as a signal to the brain that enough energy has been stored and that intake of food is no longer necessary.

• Obesity may be associated with leptin resistance due to defective leptin receptors or post receptor signaling pathways normally activated by leptin.

What are the two types of arcuate nucleus neurons that control energy balance?  

• POMC neurons release α-MSH and CART, decreasing food intake and increasing energy expenditure.

• AGRP and NPY neurons increase food intake and reduce energy expenditure.

• AGRP acts as an antagonist of MCR-4.

• Insulin, leptin, and CCK inhibit AGRP-NPY neurons and stimulate POMC-CART neurons.

• Ghrelin activates AGRP-NPY neurons and stimulates food intake.

What are the key features of ghrelin as an orexigenic signal?  

• Ghrelin is a hormone released mainly by cells of the stomach.

• Blood levels of ghrelin rise during fasting, peak just before eating, and then fall rapidly after a meal.

• Ghrelin stimulates secretion of growth hormone for GH metabolic effects.

How do CCK and stretch signals contribute to satiety?  

• CCK activates receptors on local sensory nerves in the duodenum, sending messages to the NTS via the vagus nerve that contribute to satiation and meal cessation.

• The effect of CCK is short-lived and chronic administration has no major effect on body weight.

• CCK prevents overeating during meals but may not play a major role in meal frequency or total energy consumed.

How does glucose act as an anorexigenic signal? 

• A rise in blood glucose increases firing of gluco-receptor neurons in the satiety center (ventromedial and paraventricular nuclei).

• The same increase decreases firing of gluco-sensitive neurons in the hunger center of the lateral hypothalamus.

• Some amino acids and lipid substances also affect firing of these neurons.

What mechanisms maintain normoglycemia after a meal?  

• Suppression of hepatic glucose production

• Stimulation of hepatic glucose uptake

• Stimulation of glucose uptake by peripheral tissues (muscle)

How do major organs handle glucose after a meal?  

• Liver stores glucose as glycogen and converts some to FAs, packaged as VLDLs for export to adipocytes.

• Muscle stores glucose as glycogen and converts some to lactate and gluconeogenic amino acids for export to the liver.

• Adipocytes convert glucose to glycerol-3-phosphate, a precursor of TAGs.

How do major organs handle amino acids after a meal? 

• Liver converts gluconeogenic amino acids to glycogen.

• Muscle converts amino acids to protein.

How are fats captured and stored after a meal?  

• Chylomicrons undergo hydrolysis in systemic blood vessels.

• Lipoprotein lipase on vascular endothelial cells makes FA available to adipocytes.

• Adipocytes re-esterify FAs with glycerol-3-phosphate (from glucose) for storage as TAGs.

What are the major steps of energy liberation (catabolism)?  

• Breakdown of glycogen or TAGs to simpler compounds

• For carb catabolism, step 2 is glycolysis

• For TAG, step 2 is β-oxidation

• The final common step for oxidizing carb, TAG and proteins to CO₂ are TCA cycle and oxidative phosphorylation.

How do epinephrine and glucagon mobilize energy stores?  

A) In muscle, epinephrine promotes glycogenolysis and glycolysis, producing ATP for contraction and lactate.  

B) In liver, primarily glucagon and also epinephrine trigger glucose production in the short term via glycogenolysis, and over the long term via gluconeogenesis. Hepatocytes can generate glucose and export it to the blood because they have G6Pase.  

C) In adipocytes, epinephrine triggers production of FAs and glycerol, which leave the adipocytes and enter the blood.

What are the priorities and features of fasting metabolism?  

• Priority #1 is stable supply of energy for CNS function in the form of glucose or ketone bodies. Blood-brain barrier impermeable to FAs.

• In fed state and early fasting, glucose is oxidized to meet CNS demands.

• Other major organs oxidize FAs.

• During prolonged fasting (>2 days), liver metabolizes FAs to raise levels of ketones for CNS use.

• Priority #2 – maintain protein reserves.

What metabolic processes occur during an overnight fast?  

• After a fast, decline in insulin shifts metabolism to FA mobilization.

• Body still metabolizes glucose at 7–10 g/hr.

• Free glucose only about 15–20 g (2 hours).

• Body must produce glucose at a rate to match ongoing consumption.

• 4–5 hr postprandial fall in insulin and increase in glucagon signal liver to initiate glycogenolysis and gluconeogenesis, each contributing ~50%.

• Gluconeogenesis: Cori cycle (lactate/pyruvate), glucose-alanine cycle (alanine, glutamine).

• Lipolysis: fall in insulin permits release of FA and glycerol from adipocytes.

What metabolic changes occur beyond an overnight fast?  

• Low insulin shifts liver to gluconeogenesis.

• Muscle accelerates proteolysis to contribute glycogenic AA (alanine and glutamine).

• Low insulin activates HSL so more FA and glycerol released from adipocytes.

• Increase in FA causes insulin resistance in muscle interfering with GLUT4.

• Prolonged fast: hepatic gluconeogenesis falls and shifts to renal gluconeogenesis (up to 40%).

• Body decreases use of protein for gluconeogenesis.

• Hypoinsulinemia and high glucagon increase hepatic oxidation of FAs that increase liver ketogenesis.

How are ketones synthesized and used during prolonged fasting?  

• Synthesized in the liver from FAs.

• Liver does not have β-ketoacyl CoA transferase, so acetoacetate and D-β-hydroxybutyrate enter the bloodstream.

• CNS, skeletal muscle, and cardiac muscle consume acetoacetate or D-β-hydroxybutyrate to produce 2 acetyl-CoA molecules that enter the TCA cycle.

 What metabolic changes occur during prolonged starvation?  

• As fat stores are depleted, levels of leptin decrease.

• Low leptin affects the hypothalamic-pituitary-gonadal axis decreasing LH and FSH causing anovulation.

• Protects fertile women in times of famine.

What are the three phases of protein depletion during starvation?  

1. Initial rapid depletion from use of easily mobilized protein for direct metabolism or conversion to glucose for brain metabolism.

2. Slow depletion: gluconeogenesis decreases to 1/3–1/5 previous rate → excessive fat utilization → ketone body production → brain uses ketones → partial preservation of protein stores.

3. With fat stores almost depleted, protein becomes the only remaining energy source → rapid depletion → death when proteins are depleted to about half their normal level.

 What happens to fat and carbohydrate stores during starvation?  

• Progressive depletion of tissue fat and protein.

• Fat is the prime source of energy (100× more fat energy stored than CHO), so fat depletion continues until most fat stores are gone.

• Tissues preferentially use carbohydrate for energy but stores are small, providing only enough energy for half a day.