Food Regulation

Rob Contreras, Ph.D.018 Longmire

Contreras@psy.fsu.edu

644-1751

Two Principle views of food intake control

• Food intake triggered by:– Depleted energy stores

• Less adipose tissue

• Less glucose or lipid

– Primed to eat unless inhibited• Signals from meals

• Onset not from acute need

• Caloric homeostasis

Caloric homeostasis

• Preserve cellular metabolism• Three macronutrients

– Carbohydrates, lipids, proteins

• Most tissues of the body– COH to glucose, or lipids to free fatty acids

• Liver– Lipids

• Brain– Glucose (backup - ketone bodies)

Two Distinct Metabolic States

• Prandial (fed) state– Abundance of newly ingested & absorbed

nutrients in blood

• Postabsorptive (fasted) state– Absence of entering calories from GI tract into

circulation– Reliance on metabolic fuels less recently

ingested and stored

Caloric homeostasis

During prandial state, energy is stored – as glycogen (liver and muscle) or triglycerides (adipose tissue) – facilitated by insulin – ANABOLISM

During postabsorptive state, energy is utilized for metabolism – facilitated by lack of insulin – either glycogenolysis (to produce glucose) or lipolysis (free fatty acids and glycerol) – CATABOLISM

Regulation of feeding is a balancing act – between energy storage (anabolism) and use (catabolism)

Liver: Key organ in energy traffic

• Prandial/fed– COH to glycogen– Lipogenesis (also in adipose tissue)

• Postabsorptive/fasting– Glygogenolysis– Ketogenesis– Glugoconeogenesis

• Control system = hormones + ANS

Insulin

• B cells of the pancreatic islets

• Direct proportion to blood glucose

• Also amino acids & ketone bodies

• ANS innervates pancreatic islets– PNS (ACh) stimulates secretion– SNS (NE, alpha-adrenergic) inhibits secretion

Caloric homeostasis: Insulin

Insulin is low during fasting

It is increased in cephalic phase by sight, smell and taste of food

When food enters stomach, there are direct actions of digestive hormones on insulin secretion – during gastrointestinal phase

Substrate phase results from stimulation of pancreas by metabolic fuels (mainly glucose)

Insulin serves to promote energy utilization and storage

Insulin & body fat

• More body fat, the more insulin secretion• Number of insulin receptors on adipose

tissue & skeletal tissue inversely related to adiposity

• Reciprocal relationship between insulin secretion & tissue sensitivity to insulin

• Insulin ensures efficient use & storage independent of body weight

Diabetes mellitus

• Type 1 or Insulin-dependent– High plasma glucose– Cannot be utilized & excess excreted -sweet

urine– Caused by deficiency in B cells & insulin

secretion

• Type 2 or noninsulin-dependent– 85-90% have insulin, but are obese & resistant

to insulin in promoting fuel use & storage

Two Principle views of food intake control

• Food intake triggered by:– Depleted energy stores

• Less adipose tissue

• Less glucose or lipid

– Primed to eat unless inhibited• Signals from meals

• Onset not from acute need

• Caloric homeostasis

Caloric homeostasis and food intake: SatietyMeal size does not depend on time since the last meal

– however, the size of a meal determines how long before the next one

Eating appears to be inhibited by a “satiety signal” that decreases over time

Caloric homeostasis and food intake: Satiety factors

Gastric distension serves as one satiety signal:

Rats with gastric fistulas, which do not allow fluid into the stomach, do not terminate meals as readily

Cholecystokinin (CCK) is secreted by the stomach during meals and also serves as a satiety factor

Several other molecules, including insulin, bombesin-like peptides, and glucagon may also be satiety factors – these factors control meal size

Satiety Signals• Gastric distention

– Stomach endowed with stretch receptors– Vagus to NST & area postrema

• Cholecystokinin– Secreted during meals– Receptors on Vagal afferent fibers that also convey

gastric stretch signals– CCK + stretch act synergistically to inhibit food intake

• Post-gastric– Nutritional signals from intestines to liver

• Body Weight– Forced weight loss or weight gain

Body weight and food intake: Leptin

4) Ingestion of food generates

satiety signals; L- and I-sensitive pathways

interact with satiety circuits to regulate meal

size

3) Low leptin and insulin in brain stimulate

eating and suppress energy

expenditure

2) Leptin and insulin suppress brain anabolic circuits and activate catabolic circuits

1) Leptin and insulin circulate in proportion to body fat and energy balance

Body weight and food intake: Leptin

Mutants of the Ob-Rb receptor (for leptin) are both hyperphagic and obese – i.e., they do not detect circulating leptin and overeat

Leptin is secreted by adipocytes and circulates in proportion to the amount of body fat

Overton lab goal is to determine mechanisms linking regulation of energy balance and

cardiovascular function

OverfeedingCold exposure

Caloric deprivationThermal neutrality

VO2 , sympathetic activity, heart rate, blood pressure

+

-VO2

VO2, sympathetic activity, heart rate, blood pressure

Central control of food intake

Neurons responsible for the central regulation of food intake are in several areas of the hypothalamus

These areas include the

lateral hypothalamic area (LHA),

the ventromedial hypothalamus

(VMH), the arcuate nucleus

(ARC), and the

paraventricular

hypothalamus (PVH)

Central control of food intake: VMH lesions

Lesions of the VMH produce hyperphagic, obese rats – this is not due to destruction of a “satiety center,” but to an increase in autonomic tone, which leads to increased fat deposition – i.e., a new body weight “set point” – as a result of increased insulin

These animals become hyperphagic in an attempt to maintain this new body weight

Lesion-Induced Weight LossLesions of the LH caused aphagia.

Dual Center hypothesis: VMH - satiety center; LH - hunger center.

Not due to hunger center, but to akinesia and sensory neglect; resemble Parkinson’s disease

Neuropeptides & control of food intake

• Two major classes– Anabolic

• Increased eating

• Decreased energy expenditure

• Increased body fat

– Catabolic• Reduced food intake

• Increased energy expenditure

• Loss of body fat

Central control of food intake: Signaling pathways

Arcuate neurons

NPY: neuropeptide Y – increased food intake

AgRP: agouti-related protein – increased food intake

POMC: proopiomelanocortin – precursor of -MSH

-MSH: -melanocyte-stimulating hormone – decreased food intake

CART: cocaine-amphetamine-related transcript – decreased food intake

PVN or LHA neurons

MCH: melanin-concentrating hormone – increased food intake

Orexin (hypocretin): also involved in sleep – increased food intake

CRH: corticotropin-releasing hormone – decreased food intake

Oxytocin: also involved in uterine contraction and milk letdown – decreased food intake

Catabolic pathway

• Alpha-MSH & CART– Activated by leptin & insulin– ICV-3rd = decrease food intake, increase

energy expenditure, weight loss– Bind to melanocortin receptors (MC3 & MC4)

in PVN, VMH, LH– No MC3, obese without overeating– No MC4, obese with overeating

Anabolic pathway• NPY & AgRP

– Inhibited by leptin & insulin– ICV-3rd = increase food intake, decrease energy

expenditure, weight gain– NPY neurons to PVN (NPY receptors); NPY in PVN

increase food intake– AgRP = antagonist of MC3 & MC4 receptors– AgRP to 3V, increase food intake by blocking action of

alpha-MSH on MC receptors– NPY directly stimulate anabolic pathway; AgRP

antagonizes tonically active catabolic peptides

Other peptides

• Orexin A & MCH– Injected in brain - increase in food intake– Neurons in LH, LH lesion aphagia partially due to

reduced orexin and MCH

• Oxytocin– CCK, gastric distension, hyperosmolality– ICV oxytocin decreases food intake

• CRH (stress pathway)– Icv CRH decreases food intake mediated through

oxytocin axons projecting to CNS, not pituitary

Leptin and insulin inhibit NPY/AgRP neurons and stimulate POMC/CART neurons – increased leptin and insulin lead to decreased food intake

Central control of food intake: Arcuate nucleus

Leptin and insulin deficiency activates NPY/AgRP neurons in the arcuate n.

Release of NPY and AgRP into PVN and LHA leads to increased food intake and obesity

Leptin and insulin deficiency also inhibits arcuate neurons containing POMC, leading to decrease in -MSH release and obesity

AgRP inhibits melanocortin receptors

Central control of food intake: Obesity

Arcuate neurons innervate second-order neurons in the PVN, PFA and LHA.

CRH, TRH and oxytocin neurons in the PVN produce anorexia

Orexin and MCH neurons in the PFA and LHA increase feeding

Central control of food intake: Second-order neurons

Increased Leptin and insulin levels activate POMC neurons in the arcuate n.

Release of POMC results in elevated -MSH levels and decreased food intake (anorexia)

At the same time leptin and insulin inhibit arcuate neurons containing NPY/AgRP, also leading to decreased food intake

Central control of food intake: Anorexia

Leptin and insulin inhibit NPY/AgRP neurons and excite -MSH/CART neurons in arcuate n.

NPY/AgRP neurons inhibit PVN and excite LHA, whereas -MSH/CART neurons stimulate PVN and inhibit LHA

PVN has catabolic action, LHA has anabolic action – through connections in the brainstem (e.g., NST and area postrema)

Central control of food intake: Signaling pathways

Leptin and insulin

Central control of food intake: Signaling pathways

Balance between satiety and adiposity signals

The End