Chapter 24 - Integration of Energy Metabolism

Caloric ________ is a means of regulating body weight

homeostasis

Caloric homeostasis (energy homeostasis)

the ability to maintain adequate, but not excessive, energy stores caloric homeostasis or energy homeostasis

Body mass index (BMI)

a convenient means of determining whether an individual is overweight or obese

Overweight is a BMI of more than ___ kg m–2 andobese is a BMI of more than ___ kg m–2

25; 30

Two types of signals in the gastrointestinal tract, the β cells of the _____, and fat cells

– ____-_____ signals are active during a meal

–___-______ signals report on the overall energy status of the body

pancreas; short-term; long-term

Signals of the gastrointestinal tract target the brain’s _____ nucleus, a group

of neurons in a region of the hypothalamus

arcuate

____-_____ signals relay feelings of satiety from the gut to various regions of the brain, reducing the urge to eat

short-term

Cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1)

small peptide hormones secreted into the blood by cells of the small intestine after a meal

Cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) bind to their respective __-______-coupled receptors in peripheral neurons, relaying satiety signals

G-protein

____ stimulates the secretion of pancreatic enzymes and bile salts from the gallbladder

CCK

____ enhances glucose-induced insulin secretion and inhibits glucagon secretion

GLP-1

Leptin

signal molecule that communicates the status of triacylglycerol stores

Leptin is:

– secreted by the ______

– secreted in direct proportion to the amount of fat present

– binding to its receptor increases the sensitivity of muscle and the liver to insulin, stimulates __ _______ of fatty acids, and decreases triacylglycerol synthesis

adipocytes; β oxidation

Insulin

signal molecule that communicates the status of glucose in the blood

Insulin is secreted by the _____ __ ____

pancreatic β cells

The leptin receptor is found in the arcuate nucleus of the ________ and other regions of the brain

hypothalamus

The arcuate nucleus contains two populations of neurons:

– neurons that express the appetite-stimulating (_____) peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP)

– neurons that express ________________ (POMC)

orexigenic; proopiomelanocortin

Leptin inhibits the production and release of ____ and ______, repressing the desire to eat

NPY; AgRP

Leptin triggers the proteolytic processing of _____, yielding a variety of signal molecules including melanocyte-stimulating hormone (MSH)

POMC

_____ activates appetite-suppressing (anorexigenic) neurons, inhibiting food consumption

MSH

______ inhibits MSH activity by binding to the MSH receptor and acting as an antagonist

AgRP

Insulin appears to inhibit NPY/AgRP-producing neurons, inhibiting food _______

consumption

Adipokines

signal molecules that regulate a host of physiological processes

Leptin and adiponectin are examples of ________

adipokines

Ob/ob mice

mice that completely lack leptin, resulting in their extreme obesity

Adipokine produced by adipocytes that is secreted in proportion to decreases in fat mass

adiponectin

Adiponectin

functions to increase the sensitivity of the organism to insulin

Leptin and adiponectin exert their effects through ____-activated protein kinase (_____)

AMP; AMPK

Key regulatory enzyme that is active when AMP levels are elevated and ATP levels are diminished

AMP-activated protein kinase (AMPK)

AMP-activated protein kinase (AMPK) leads to a decrease in anabolism and an increase in _______ (fatty acid oxidation)

catabolism

In insulin-resistant obese animals, leptin levels ______ and adiponectin levels _______

increase; decrease

RBP4 and resistin

hormones produced by adipocytes that promote insulin resistance

Enlarged adipocytes resulting from obesity may secrete higher levels of RBP4 and resistin, contributing to _______ resistance

insulin

Adipokines help to maintain systemic ___ and ______ homeostasis

lipid; glucose

The failure to respond to the appetite- suppressing (anorexigenic) effects of leptin

leptin resistance

Leptin resistance may contribute to ______

obesity

Suppressors of cytokine signaling (SOCS)

proteins that fine-tune hormonal systems by inhibiting receptor action

Suppressors of cytokine signaling (SOCS) binds to phosphorylated ____ residues, disrupting the insulin-signaling pathway

Tyr

Leptin:

a. is secreted by pancreatic β cells.

b. is secreted in proportion to decreases in fat mass.

c. exerts its effects through AMP-activated protein kinase (AMPK) to increase the organism’s sensitivity to insulin.

d. inhibits production and release of neuropeptide Y (NPY) and agouti-related peptide (AgRP).

e. levels decrease in insulin-resistant obese animals.

d

Fasted–fed cycle

a physiological condition experienced after an evening meal and throughout the night’s fast

The fasted–fed cycle has three stages:

– ___-____ (post-prandial) state

– ____ _____ (postabsorptive) state

– _____ state

well-fed; early fasting; refed

Glucose homeostasis

constant blood-glucose concentration

Glucose homeostasis is maintained during the fasted–fed cycle by ____ and ____

insulin; glucagon

State that immediately follows the absorption of glucose from the previous meal when blood-glucose concentration begins to drop

postabsorptive (fasted) state

The postabsorptive (fasted) state leads to a ______ in insulin secretion and a ____ in glucagon

decrease; rise

Glucagon:

– _______ glycogen breakdown

– _____ glycogen synthesis

– _____ fatty acid synthesis

– _______ the gluconeogenic state in the liver

– ____ glycolysis

stimulates; inhibits; inhibits; stimulates; blocks

Glucagon’s actions are mediated by _____-activated protein kinases.

cAMP

Activation of the cyclic AMP cascade results in:

– _____ phosphorylase a activity

– ______ glycogen synthase a activity

higher; lower

The net result of glucagon action is the marked increase of the release of glucose by the _____

liver

The refed state occurs at the end of a long ____

fast

After a long fast, the liver remains in a gluconeogenic mode, replenishing the liver’s ______ stores

glycogen

After glycogen stores are replenished, the liver processes excess glucose for ____ ____ synthesis

fatty acid

Increased blood-glucose levels lead to increased insulin and decreased glucagon secretions. Does this lead to glycogen synthesis or breakdown in muscle and liver?

glycogen synthesis

Disruption of body weight and glucose homeostasis regulation commonly results in _____

obesity

Diabetes mellitus

a disease resulting from disruption of caloric homeostasis

Diabetes mellitus is characterized by overproduction of ______ by the liver and underutilization by other organs and named for the common symptom of excessive _______

glucose; urination

Diabetes caused by destruction of the insulin-secreting β cells of the pancreas

type 1 diabetes (insulin-dependent diabetes)

Type __ diabetes is typically an autoimmune disorder and begins before age 20

1

Insulin resistance

characteristic by which individuals are poorly responsive to insulin

diabetes caused by insulin resistance

type 1 diabetes

Type __ diabetes arises later in life than type 1, obesity is a significant predisposing factor, and accounts for 90% of the cases in the world

2

Upon insulin ______, the receptor autophosphorylates on Tyr residues, generates binding sites for insulin- receptor substrates (IRSs)

binding

Insulin leads to:

– ______ of glucose from the blood

– _______ of glycogen synthase

– enhanced glycogen synthesis

absorption; activation

The insulin-signaling cascade is turned off by:

– breakdown of _____

– ______ of the insulin receptor and destruction of PIP3 by phosphatases

– inactivation of the ____ protein by phosphorylation on Ser residues by specific Ser/Thr kinases

– interactions of _____ proteins with the insulin receptor and IRS-1

insulin; deactivation; IRS; SOCS

Cluster of pathologies, including insulin resistance, hyperglycemia, and dyslipidemia (high blood triacylglycerol levels), that often develop together

metabolic syndrome

Metabolic syndrome is

thought to be a predecessor of type 2 diabetes

Hepatic steatosis

condition in which tissues other than adipose tissue accumulate fat

Hepatic steatosis often occurs in ____ and ______ and results in insulin resistance and pancreatic failure

liver; muscle

Excess fatty acids are reincorporated into ________

triacylglycerols

Excess fatty acids being reincorporated into triacylglycerols leads to _____ fat accumulation

• Cytoplasmic levels of diacylglycerol _______, which activate protein kinase C (PKC)

• Cytoplasmic levels of ceramide _______, which inhibit glucose uptake and glycogen synthesis by inhibiting protein kinase B (PKB).

• The net result is diet-induced ______ resistance.

cytoplasmic; increase; increase; insulin

Excess fat can disrupt signal-transduction pathways and lead to insulin _______

insensitivity

Insulin resistance in muscle facilitates _______ failure

pancreatic

A primary function of the pancreas is to respond to the blood glucose levels by secreting _____

insulin

When blood glucose levels are ____, glucose enters pancreatic β cells through ______ and pancreatic glucokinase traps glucose within the cell

high; GLUT2

β cells metabolize glucose to CO2 and H2O through ____ ________, generating ATP

cellular respiration

The ATP/ADP ratio _______ closes an ATP-sensitive K+ channel preventing K+ from flowing out of the cell

increasing

The change in the cellular ionic environment opens a voltage-sensitive Ca2+ channel, causing ______ release

insulin

Insulin release by the _______ is regulated by blood glucose concentration, using ____ as a second messenger

pancreas; ATP

Endoplasmic reticulum stress ______ the unfolded protein response

initiates

β cells respond to insulin ______ by making and secreting more insulin

resistance

Condition by which the ability of the ER to process all the insulin and proinsulin becomes compromised

endoplasmic reticulum (ER) stress

Endoplasmic reticulum (ER) stress leads to the accumulation of _____ or _______ proteins

unfolded; misfolded

Unfolded protein response (UPR)

signal pathway initiated in response to ER stress

Steps in the Unfolded Protein Response

Step 1: General protein synthesis is ______.

Step 2: Chaperone synthesis is ______.

Step 3: Misfolded proteins are removed from the ER and are delivered to the proteasome for _____.

Step 4: If the first three steps fail to alleviate the ER stress, programmed cell death is triggered, leading to β cell death and full-fledged type __ diabetes.

inhibited; stimulated; destruction; 2

Which step leads to the increase in cytoplasmic levels of a second messenger that activates PKC?

Triacylglycerols increasing

Metformin (Glucophage) activates ____, promoting the _____ of fats, inhibiting fat synthesis and storage, stimulating glucose uptake and storage by muscle, and inhibiting _________ in the liver

AMPK; oxidation; gluconeogenesis

In type 1 diabetes, insulin production is insufficient because of autoimmune destruction of ______ __ ____

pancreatic β cells

A lack of insulin can lead to diabetic ______.

ketosis

A lack of insulin leads to the uncontrolled breakdown of lipids and proteins, resulting in the _______ state

• The large amounts of _____ ____ produced cannot enter the citric acid cycle because there is insufficient oxaloacetate.

• Acetyl CoA is converted into _____ ______, overwhelming the kidneys and can lead to diabetic ketosis

ketogenic; acetyl CoA; ketone bodies

Skeletal muscle:

– accounts for ~40% of total ____ ____ and ~35% of resting ______ _____

– is the largest target tissue for ______

body mass; metabolic activity; insulin

A sprint is powered by stored _____, creatine phosphate, and the anaerobic ________ of muscle glycogen

ATP; glycolysis

Sprinting is powered by ____-_____ muscle fiber (type IIb) specialized for anaerobic glycolysis

fast-twitch

Sprinting cannot be sustained because:

– ______ _______ is consumed within a few seconds

– lactate produced contributes to ______

creatine phosphate; acidosis

Respiratory quotient (RQ)

The ratio of CO2 produced to O2 consumed

The respiratory quotient (RQ) can be used to determine the contribution of each fuel as a function of _______ intensity

exercise

The RQ for glucose is ___ and the RQ for palmitate is _____

1 ; 0.7

As aerobic exercise intensity increases, RQ rises from 0.7 (only fats are used) to ____ (only glucose is used)

1.0

When muscle glycogen is depleted, the power output of the muscle falls to approximately____ of maximum

50%

Low blood-sugar leads to a high glucagon/insulin ratio, which mobilizes fatty acids for _________ by β oxidation

degradation

Elevated acetyl CoA levels ______ pyruvate dehydrogenase complex activity

decrease