Regulation of Energy Intake & Body Weight Regulation Flashcards Preview

Proteins Biochem > Regulation of Energy Intake & Body Weight Regulation > Flashcards

Flashcards in Regulation of Energy Intake & Body Weight Regulation Deck (38)
Loading flashcards...
1

The body has elaborate mechanisms regulating food intake and energy balance.

a. Animals, including humans, tend to maintain a relatively constant body weight over extended periods of time.
i. Thus, like body temperature, there appear to be endogenous mechanisms maintaining a ‘set point’ for body weight.

b. However, unlike the set point for body temperature, the set point for body weight varies considerably from individual to individual and may change within an individual.

c. Nevertheless, the mechanisms regulating food intake and energy expenditure appear to operate to defend each individual’s current “set point”.

d. Experimentally this feature can be seen when animals are either food restricted or force-fed for a period of time to reduce or increase body weight
i. Once the stimulus is terminated, the animal’s weight returns to control values.

2

Animal and Set point

a. Animals tend to adjust their food intake to achieve a normal body weight.

b. The graph shows a schematized growth curve for 3 groups of rats that were either (a) force-fed, (b) allowed free access to food, or (c) food restricted for the period between the arrows.

c. Note that the animals slowly returned to “normal” weight when allowed free access to food

3

Short- and Long-term physiologic/ homeostatic regulators

a. In understanding the control of body weight. there are both short- and long-term physiologic/ homeostatic regulators
i. for each regulator a variety of neural and blood-borne factors determine whether feeding will be prompted or inhibited.

b. A signal that produces satiety after a single meal is very different from a signal that provides long-term regulation of body weight.
i. The former (satiety) controls meal size and short-term fuel availability; the latter is a determinant of adiposity.


d. In addition, non-physiologic or non-homeostatic signals are extremely important in the regulation of energy balance.
i. This is especially true in humans.

e. These include reward and motivational mechanisms, learned behaviors, emotions, social context, and environmental cues to name a few. Furthermore, there are likely important interactions between homeostatic and non-homeostatic signals

4

The hypothalamus is intimately involved in both the control of short- and long-term regulation of body weight.

The paraventricular nucleus (PVN), ventromedial nucleus (VMN), arcuate nucleus (Arc), and lateral hypothalamus (LH) regulate food intake and disposition by processing information concerning peripheral energy stores and then stimulating or inhibiting feeding or altering gastric motility and food metabolism/utilization.

5

What four ares of the brain... regulate food intake and disposition by processing information concerning peripheral energy stores and then stimulating or inhibiting feeding or altering gastric motility and food metabolism/utilization.

The paraventricular nucleus (PVN), ventromedial nucleus (VMN), arcuate nucleus (Arc), and lateral hypothalamus (LH)

6

Short-Term Regulation of Food Intake

a. Short term regulation of food intake involves cues to initiate feeding (hunger) and cues to stop feeding (satiety).

b. Thus, these are the signals involved in potentially determining meal size and frequency.

c. Early studies identified the lateral hypothalamus as the ‘hunger center’ and the ventromedial nucleus as the ‘satiety center’.

7

The Lateral Hypothalamus (LH)

a. Stimulation of the lateral hypothalamus (LH) produces voracious eating, even in a food replete animal, and lesions in this region produced aphagia (no eating).

b. Two peptides have been identified that are expressed in the brain only by neurons in the LH: melanin concentrating hormone (MCH) and orexins (also known as hypocretins).

c. These peptides induce feeding when injected into the CNS. The MCH and orexin neurons in the LH have very similar projection patterns, including the brainstem motor systems that support behaviors like chewing, licking, and swallowing.

d. These include cranial nerve motor neurons in the trigeminal, facial, and hypoglossal motor nuclei, as well as the reticular areas that surround them and which constitute pattern generators for these behaviors.

e. The MCH and orexin neurons also innervate sympathetic and parasympathetic preganglionic nuclei in the medulla and the spinal cord.

8

What doe stimulation of the lateral hypothalamus cause? What about a lesion to the lateral hypothalamus

Stimulation of the lateral hypothalamus (LH) produces voracious eating, even in a food replete animal,

Lesions in this region produced aphagia (no eating).

9

Two peptides have been identified that are expressed in the brain only by neurons in the Lateral Hypothalamus

*Important slide

Melanin Concentrating Hormone (MCH) and Orexins (also known as hypocretins).

a. These peptides induce feeding when injected into the CNS.

b. The MCH and orexin neurons in the LH have very similar projection patterns, including the brainstem motor systems that support behaviors like chewing, licking, and swallowing.
i. These include cranial nerve motor neurons in the trigeminal, facial, and hypoglossal motor nuclei, as well as the reticular areas that surround them and which constitute pattern generators for these behaviors.

c. The MCH and orexin neurons also innervate sympathetic and parasympathetic preganglionic nuclei in the medulla and the spinal cord.

10

Ventromedial Nucleus (VMN)

a. Opposite effects are seen in the ventromedial nucleus (VMN) compared to the lateral hypothalamus

b. Evidence that the VMN acts as a ‘satiety’ center comes from the observation that stimulation of this region results in cessation of eating even in hungry animals.

c. Animals with lesions in this region eat excessively and become obese.
i. Lesioned animals may reach 3-4 times normal weight within several months.
ii. Once this weight is reached, the animals reduce their food intake to simply maintain their increased weight.
iii. If they are force-fed to further increase their weight, they subsequently reduce their eating to lose weight back to the post-lesion level. If they are food-restricted, they subsequently eat to regain the weight.

d. Thus, VMN lesions have the effect of “resetting” the regulated weight to a higher level.

11

What does the Ventromedial Nucleus do?

a. Evidence that the VMN acts as a ‘satiety’ center comes from the observation that stimulation of this region results in cessation of eating even in hungry animals.
i. stimulation of VMN= stops eating, lowers weight

b. Animals with lesions in this region eat excessively and become obese.
i. Lesioned animals may reach 3-4 times normal weight within several months.
ii. Once this weight is reached, the animals reduce their food intake to simply maintain their increased weight.

12

Although the VMN and LH were the first hypothalamic regions recognized for their role in regulating appetite and satiety, the Arcuate and Paraventricular nuclei are also extremely important.

*Large Summary*

a. The arcuate nucleus contains “first order” neurons that promote either food intake or satiety.

b. Activation of arcuate neurons that produce both neuropeptide Y (NPY) and agouti-related peptide (AgRP) promote feeding while activation of the arcuate neurons that produce both α-melanocyte stimulating hormone (α-MSH) and cocaine and amphetamine-related transcript (CART) promote satiety.

c. Remember, α-MSH is a product of the proopiomelanocortin (POMC) precursor molecule.
i. These two neuron populations innervate many of the same targets in the hypothalamus including the paraventricular nuclei (PVN) and LH.
ii. . In addition, the α-MSH/CART neurons directly innervate sympathetic preganglionic neurons in the spinal cord.


d. α-MSH activates melanocortin receptors (MCR) while AgRP blocks the effect of α-MSH at these receptors.
i. MCRs are expressed in PVN and LH as well as by preganglionic sympathetic and parasympathetic neurons in the medulla and spinal cord.

e. Activation of MCRs induces satiety.
i. NPY increases hunger when injected into the hypothalamus and decreases energy expenditure (via inhibition of the sympathetic nervous system and perhaps by inhibition of thyroxin and growth hormone secretion).

f. Thus, the NPY/AgRP neurons are thought to constitute a potent feeding system that is actively opposed by the α-MSH/CART satiety system.
i. These neurons express receptors for peripherally generated hormones (see below) that participate in regulation of food intake, and these hormones can alter the balance between these opposing systems.

13

Arcuate Neuron and what it creates

Arcuate Neuron's products:

1. Feeding molecules: both Neuropeptide Y (NPY) and agouti-related peptide (AgRP) promote feeding
i. NPY increases hunger when injected into the hypothalamus and decreases energy expenditure (via inhibition of the sympathetic nervous system and perhaps by inhibition of thyroxin and growth hormone secretion)
ii. AgRP blocks the effect of α-MSH at these receptors

2. Satiety Molecules: α-melanocyte stimulating hormone (α-MSH) and cocaine and amphetamine-related transcript (CART)
i. the α-MSH/CART neurons directly innervate sympathetic preganglionic neurons in the spinal cord
ii. α-MSH activates melanocortin receptors (MCR), Activation of MCRs induces satiety


*MCRs are expressed in PVN and LH as well as by preganglionic sympathetic and parasympathetic neurons in the medulla and spinal cord. Activation of MCRs induces satiety

14

What are the feeding molecules that the Arcuate Nucleus creates?

Feeding molecules: both Neuropeptide Y (NPY) and agouti-related peptide (AgRP) promote feeding

a. NPY increases hunger when injected into the hypothalamus and decreases energy expenditure (via inhibition of the sympathetic nervous system and perhaps by inhibition of thyroxin and growth hormone secretion).

b. Thus, the NPY/AgRP neurons are thought to constitute a potent feeding system that is actively opposed by the α-MSH/CART satiety system.

15

What are the Satiety molecules that the Arcuate Nucleus creates?

Satiety Molecules: α-melanocyte stimulating hormone (α-MSH) and cocaine and amphetamine-related transcript (CART)

a. The α-MSH/CART neurons directly innervate sympathetic preganglionic neurons in the spinal cord

b . α-MSH activates melanocortin receptors (MCR), Activation of MCRs induces satiety
-AgRP blocks the effect of α-MSH at these receptors

c. MCRs are expressed in PVN and LH as well as by preganglionic sympathetic and parasympathetic neurons in the medulla and spinal cord. Activation of MCRs induces satiety.

16

Neuropeptide Y (NPY) and Agouti-related peptide (AgRP)

versus

α-melanocyte stimulating hormone (α-MSH) and cocaine and amphetamine-related transcript (CART)



*these are all products of the arcuate nucleus

The NPY/AgRP neurons are thought to constitute a potent feeding system that is actively opposed by the α-MSH/CART satiety system.
i. NPY increases hunger when injected into the hypothalamus and decreases energy expenditure (via inhibition of the sympathetic nervous system and perhaps by inhibition of thyroxin and growth hormone secretion).

b. The α-MSH/CART neurons activates melanocortin receptors (MCR); activation of MCRs induces satiety
i. AgRP blocks the effect of α-MSH at these receptors
ii. MCRs are expressed in PVN and LH as well as by preganglionic sympathetic and parasympathetic neurons in the medulla and spinal cord

17

GI Signals

a. Both hormonal and neural signals generated in the GI tract participate in short-term regulation of food intake.

b. Ghrelin is a 28 a.a. peptide hormone secreted from the stomach that induces feeding.
i. Its blood levels peak prior to a meal, although the factors stimulating its release are poorly understood.

c. Ghrelin receptors are located in the arcuate nucleus, and ghrelin appears to activate the NPY/AgRP arcuate neurons

18

Ghrelin

a. Ghrelin is a 28 a.a. peptide hormone secreted from the stomach that induces feeding.
i. Its blood levels peak prior to a meal, although the factors stimulating its release are poorly understood.

b. Ghrelin receptors are located in the arcuate nucleus, and ghrelin appears to activate the NPY/AgRP arcuate neurons

c. The NPY/AgRP neurons are thought to constitute a potent feeding system
i. NPY increases hunger when injected into the hypothalamus and decreases energy expenditure

19

Several satiety signals also originate from the GI tract.

a. Information about gastric distension as well as hepatic levels of glucose and lipids are carried by vagal afferents to the nucleus of the tractus solitarius (NTS) in the brainstem and are relayed to the PVN, arcuate nucleus, and LH, as well as to the amygdala and visceral sensory thalamus.
i. Information from the thalamus is transmitted to the visceral sensory cortex and provides conscious appreciation of gastric fullness.

b. The duodenum signals the presence of nutrients to the brain via the release of cholecystokinin (CCK).
i. CCK activates vagal afferents in the peritoneum and also acts via the area postrema to activate brainstem pathways projecting to the hypothalamus.

c. Glucagon-like peptide (GLP-1) is synthesized in the L-cells of the distal ilium in response to nutrients and is an important incretin hormone.
i. GLP-1 also acts on receptors in the area postrema via the NTS to activate pathways leading to reduced food intake.

c. Peptide YY (PYY) is also released from L cells of the distal ilium in response to nutrients.
i. PYY appears to have its anorexic effects by inhibiting hypothalamic NPY/AgRP neurons.

20

Cranial Nerve afferent information from the GI Tract

a. Information about gastric distension as well as hepatic levels of glucose and lipids are carried by vagal afferents to the nucleus of the tractus solitarius (NTS) in the brainstem and are relayed to the PVN, arcuate nucleus, and LH, as well as to the amygdala and visceral sensory thalamus.

b. Information from the thalamus is transmitted to the visceral sensory cortex and provides conscious appreciation of gastric fullness.

21

CCK, GLP-1, and Peptide YY

a. The duodenum signals the presence of nutrients to the brain via the release of cholecystokinin (CCK).
i. CCK activates vagal afferents in the peritoneum and also acts via the area postrema to activate brainstem pathways projecting to the hypothalamus.

b. Glucagon-like peptide (GLP-1) is synthesized in the L-cells of the distal ilium in response to nutrients and is an important incretin hormone.
i. GLP-1 also acts on receptors in the area postrema via the NTS to activate pathways leading to reduced food intake.

c. Peptide YY (PYY) is also released from L cells of the distal ilium in response to nutrients.
i. PYY appears to have its anorexic effects by inhibiting hypothalamic NPY/AgRP neurons.

22

cholecystokinin (CCK)

a. The duodenum signals the presence of nutrients to the brain via the release of cholecystokinin (CCK).

b. CCK activates vagal afferents in the peritoneum and also acts via the area postrema to activate brainstem pathways projecting to the hypothalamus.

23

Glucagon-like peptide (GLP-1)

a. Glucagon-like peptide (GLP-1) is synthesized in the L-cells of the distal ilium in response to nutrients and is an important incretin hormone.

b. GLP-1 also acts on receptors in the area postrema via the NTS to activate pathways leading to reduced food intake.

24

Peptide YY (PYY)

a. Peptide YY (PYY) is also released from L cells of the distal ilium in response to nutrients.

b. PYY appears to have its anorexic effects by inhibiting hypothalamic NPY/AgRP neurons.
i. NPY/AgRP normally induce feeding/hunger, will be inhibited by PYY

25

Glucose

a. Glucose has long been recognized to participate in both hunger and satiety.

b. Hypoglycemia stimulates eating and hyperglycemia inhibits eating.

c. Glucose sensitive neurons are located in the VMN and LH as well as elsewhere in the brain (arcuate nucleus, area postrema and NTS).
i. However, the glucose-sensitive neurons in the VMN are stimulated by hyperglycemia while the glucose-sensitive neurons in the LH are inhibited by glucose.

d. The importance of the glucose sensitive cells in VMN for the regulation of food intake and body weight is demonstrated by the observation that obesity develops in mice after selective destruction of these cells.
i. These same neurons are also affected by other circulating nutrients.

e. Although the involvement of these cells in feeding and satiety is recognized, the relative importance of ‘normal’ blood glucose levels in the regulation of appetite and body weight regulation is still under considerable debate.

26

Glucose has long been recognized to participate in both hunger and satiety.

a. Hypoglycemia stimulates eating and hyperglycemia inhibits eating.

b. Glucose sensitive neurons are located in the VMN and LH as well as elsewhere in the brain (arcuate nucleus, area postrema and NTS).

c. However, the glucose-sensitive neurons in the VMN are stimulated by hyperglycemia while the glucose-sensitive neurons in the LH are inhibited by glucose.

e. The importance of the glucose sensitive cells in VMN for the regulation of food intake and body weight is demonstrated by the observation that obesity develops in mice after selective destruction of these cells.
i. These same neurons are also affected by other circulating nutrients.

27

In addition to the short-duration physiological processes, there are long-term controls that provide information to balance caloric intake with energy expenditure.

a. These result in remarkably stable body weight over weeks, months and even years.

b. If you doubt this, consider the following.
i. The average weight gain for males between the ages of 20 and 60 years has been estimated to be about 20 pounds, or 1/2 pound per year.
ii. It requires a yearly excess intake of 1560 Kcal to deposit this 1/2 pound.
iii. Dividing 1560 Kcal by 365 days gives the daily excess caloric intake required to deposit this amount of fat as 4.27 Kcal/day.

c. This equates to one extra very small nibble on a slice of white bread (a slice of white bread has about 50 Kcal)!

d. It is extremely unlikely that energy balance could be maintained this precisely without a system that continually matches energy intake and expenditure.

28

What are the long-term controls on appetite?

a. Gaining or losing weight in an adult is primarily a matter of gaining or losing total body fat, which suggests that if total body weight (fat) is regulated over the long-term via control of appetite, there must be some signal from adipose cells to the appetite control system in the brain that provides information about adipose tissue mass.

b. Early evidence that a signal from adipose tissue suppresses appetite was that surgically removing adipose tissue (lipectomy) in rats resulted in increased appetite, as if the reduction in total body fat had reduced the level of an appetite-depressing signal.

c. Another finding was that serum from rats made obese by being fed a high-fat diet had an appetite-depressing effect when injected into control rats.

29

Perhaps the most compelling early evidence for a circulating factor associated with increased adipose tissue mass came from parabiotic animal experiments.

a. In these experiments two rats were joined surgically in the abdomen in such a way that there was exchange of blood constituents between the rats.
i. (This is a classic approach for demonstrating hormonal actions.)

b. If one of a pair of such parabiotic rats was made fat (via overeating induced by lesion of the ventromedial hypothalamic "satiety center" or electrical stimulation of the lateral hypothalamic "hunger center" or by force-feeding by stomach tube), the other rat began to under eat and lose weight sometimes to the point of death by starvation.

c. This suggested strongly that there is a circulating factor in fat rats that suppresses appetite.
i. It was subsequently discovered that cultured fat cells from obese rats produce a protein or peptide factor that can depress appetite when injected into the brain ventricles of normal rats.

30

Leptin and the leptin-receptor

Large summary

a. In 1994, the ‘satiety hormone’ from adipose tissue was identified when the gene that is defective in an obese strain of mice, the ob/ob strain, was cloned.

b. Recombinant protein made from the normal gene was named "leptin."

c. Obese mice of the ob/ob type are deficient in leptin and can be cured of their obesity by systemic administration of this protein.

d. Systemic injection of leptin into normal mice also results in decreased appetite (and increased metabolic rate), resulting in weight loss.
i. Minute amounts of leptin injected directly into the brain ventricles also result in weight loss, suggesting that the site of action of systemically-injected leptin is the brain.

e. It has been further demonstrated that another strain of obese mice, the db/db strain, have a supernormal amount of circulating leptin, but are insensitive to it.
i. This strain has a mutation in the leptin receptor.

f. The leptin receptor protein is expressed in the arcuate and VMN (as well as other regions).
i. Leptin inhibits the NPY/AgRP neurons in the arcuate and activates the α-MSH/CART neurons.
iii. Thus, it activates the satiety circuits and inhibits the feeding circuits