04/19/23 ERC-Zahedi 1

ENERGY BALANCE

S. Zahedi

Endocrine Research CenterResearch Institute for Endocrine Sciences

Shaheed Beheshti University of Medical Sciences2nd obesity Congress

29-30- Oct. 2009Tehran-Iran

One of the myths of the modern world is that health is largely determined by individual choice.

Barry R. Bloom (2000)

Each individual has his or her predetermined energy ration= if some body uses slowly, lasts longer

OBESITY

Genes

Monogenic syndromes Susceptibility genes(many genes, each with

small effect)

Physical activity Food intakeEnvironment/Lifestyle

ENERGY BALANCE

Energy Balance

Basal metabolism: energy expenditure of a subject relaxed and at rest, at thermoneutrality, 8–12 hours after last food ingestion.

Adaptive thermogenesis: energy dissipated as heat in response to environmental changes.

Control systems in the body

Nervous

Hormonal

Feeding Experiments

• Forced feeding• Measure size of food• Introduce food for some time more than what the animal consumes ( force

feeding)• Will lead to weight gain• If you remove force feeding, will lead to reduced food consumption for some time• Will return to previous value

• Restricted food ration• Measure size of food• Introduce restricted food size for some time (less than what the animal

consume• Will lead to weight loss• If you remove restricted feeding, will lead to increased food

consumption for some time• With return to previous value

Brain Lesioning Studies

Profound obesity from destruction of hypothalamic:1. Paraventricular nucleus (PVN)2. Ventromedial nucleus (VMN)3. Dorsomedial nucleus (DMN)

Anorexia/weight loss from destruction of:4. Lateral hypothalamic area (LHA)

Brain Centers in Energy Homeostasis

ARC: arcuate nucleus, PVN: paraventricular nucleus, PFA: perfornical area, FX: fornix, LHA: lateral hypothalamic area, VMN: ventromedial nucleus, DMN: dorsomedial nucleus, AM: amygdala, CC: corpus callosum, OC: optic chiasm, SE: septum, TH: thalamus, 3V: third ventricle

NPYAgRP

Phases of food in GI tract• Cephalic Phase

– CNS is involved– Vagus nerve

• Gastric Phase– Presence of the food in the stomach ( Involvement of ENS– Vagus nerve is involved ( Vago-Vagal Reflex)

• Enteric Phase– ENS is involved– Vagus nerves is involved– GI Hormones

Food intake control stages

• Very short term

• Short term

• Long term

Food intake control stages Very short term

Sham satiety Pure nervous Ends food consumption during each meal

Eosophagus Mechanoreceptors Counts the bolus Convey the signals to CNS

Stomach Mechanoreceptors Counts the bolus Stimulated by stretch Convey the signals via vagus nerve Vagotomy remove this signal

Short term Through satiety

Glucose ( Glucostatic) AA ( aminostatic) Temp.( thermostatic) Plasma osmolarity ( Osmostatic) GI hormones

Long term Contents of Adipose Tissue Signals from fat cells to CNS Controls energy content of the body (body weight)

SET POINT HYPOTHESIS Blood-borne factor(s) mediate(s) control of body weight at a

defined level (the "set point") by interacting with the hypothalamus

Factors regulate: food intake (appetite) energy expenditure (level of activity and body temperature)

Several discrete genetic loci and their protein products identified

Efficiency or defect in one of these may disrupt normal weight control leading to dramatic weight gain and associated syndromes (e.g., NIDDM)

80% of NIDDM cases are associated with obesity

Model of food intake: lipostat (adipostat) concept = signals proportional to the size of fat stores integrate with other regulators of food intake

Depletion of energy stored in adipose tissue increases food consumption => larger meal sizes

Food intake is regulated within a lipostatic system for energy homeostasis

Hypothalamusarcuate nucleus

Leptinreceptor

JAK-STAT3Appetite issuppressed

CNS

Adipose

Adipose storesare HIGH

Leptin

Periphery

+

Metabolic activity increases to burn fat

MSHfrom POMC neurons

AGRP from hunger neuronsBlock MSH binding

Appetite isenhanced

CNS

Adipose

Adipose storesare low

Leptinreceptor

JAK-STAT3

Leptin

Periphery

Metabolic activity decreases limiting fat burning

+

Hypothalamus

MSH

Primary Neurons

Control of Feeding Behavior and Satiety

Figure 24.23

Conclusion

• Physiological control of food intake and energy intake are very efficient, If we leave the m alone, they will work perfectly.

• Any deviation in their activity whatever is the reason will obviously change the balance in away that we do not want

• Some of these deviations may have pathological nature, but some of them are because of our behavior, it is better to leave them to themselves.!!!!!!!!!!!!!!!

Ghasemi 24

Inputs

Factor CNS Effect Peripheral Effect

-MSH (melanocortin) satiety Increase energy expenditure

Cocaine-and amphetamine-regulated transcript (CART)

satiety -------

Serotonin satiety (and other effects)

-------

CCK-PZ satiety gallbladder contraction/ pancreatic enzyme secretion

GLP-I satiety stimulates insulin secretion

agouti-related peptide (AGRP)

hunger -------

neuropeptide Y (NP-Y) hunger -------

galanin hunger (for fatty food)

-------

orexins A and B hunger -------

Table I: Neural control of appetite

Profusion of Peripheral Signals

DVC: Dorsal Vagal Complex

Dominant Inputs to Primary Neurons

Inputs

Signals Produced by Primary Neurons

Hormone Made By: Talks To : Signal NotesAgrp(Agouti)

Arc N(Melanocytes)

Mc3/4r @ LH and PVN(mc1r)

Empty! Mc4r most common monogenic human obesity (4%);Ay mouse model

Npy Arc N and otherareas of brain

Empty!

-MSH Arc N, NTS &pituitary

Mc3/4r @ LH and PVN Full! Product of Pomc w/ ACTH and -endorphin; autocrinenegative feedback via Mc3r

Cart Arc N Full! Cocaine and amphetamine regulated transcript (misnomer)

Outputs to Body and Higher Brain

Hormone Made By: Talks To : Signal NotesMch LH Empty! “fuel-guage->fuel-pump”

HypocretinOrexin 1/2

LH Empty! Hormone and receptor knockouts produce narcolepsy

Trh PVN Pituit.(Tsh)->Thyroid(Thr) Full! “fuel-guage->gas-pedal”; Mc4r ant. & MSG block lep.Trh

Dopamine SNPC/VTAmotor/reward

D1-D4 @caudate-putamen/nucleus accumbens

Empty! Parkinson wasting; “know hungry but don’t care”; C-Pdopamine production fixes feeding but not locomotion;behaviors of motivation/reward/pleasure; no hyp. projections

AcCholine Chrm3 muscarinic receptor Empty! Chrm3 respond to Mch but not Agrp (potentiation)

Endocrine Efferent Outputs

Dopamine and Outputs to Striatum

SNPC: substantia nigra pars compactaVTA: ventral tegmental area

(motor activity)

(motivation/reward)

Opioids and amphetamines remove a GABAnergic block on dopamine production. These drugs suppress appetite, and were initially used to treat obesity. In humans, BMI is anti-correlated with #D2 receptors in the striatum.

Bias Toward Weight Gain

1. Arc destruction causes weight gain.

2. Response to weight loss bidirectional; weight gain unidirectional.

3. Mc4r=> weight gain whereas npy=>no weight loss.

4. AgRP/Npy neurons are more sensitive to adiposity signals than Pomc/Cart neurons.

HOWEVER:

5. Anabolic pathways are required for intact responses to negative energy balance (IDDM causes negative energy balance in Npy-/- mice).

6. Anabolic pathways are required for response to decreased leptin (Npy-/- over ob/ob mice show reduced hyperphagia).

Currently Approved Therapies

1. Orlistat (interferes with fatty acid hydrolysis); => moderate clinical effects; side effects include gas/diaharrea.

2. Sibutramine (central norepinephrine/serotonin RI); => moderate clinical effects; side effects include tachycardia and hypertension.

3. Roux-en-Y gastric bypass (absorption and hormonal).

4. Rimonabant (Acomplia; CR1 endocannabinoid antagonsist).

Adipokines• Adipokine is a term applied to biologically active substances found in the adipocytes

of white fat (adipose) tissue. • Adipokines may be synthesized at other sites and participate in functions unrelated

to those within adipose tissue. • Many exert proinflammatory effects and may be causally involved in obesity and

diabetes. • These adipokines include

– leptin,

– tumor necrosis factor alpha (TNFα), – interleukin (IL)-6, – plasminogen activator inhibitor-1 (PAI-1),– angiotensinogen, – and resistin. – A few others, particularly

• adiponectin and transforming growth

• factor beta-1 (TGF-β1), are anti-inflammatory and may exert protective functions against metabolic disturbance.

Leptin receptors in the CNS

• High levels of leptin receptor mRNA and protein are expressed in both rodent and human

• In Hypothalamus: – (ventromedial hypothalamus, – arcuate nucleus– and dorsomedial hypothalamus) that are involved

in regulating energy homeostasis are highly enriched with leptin receptors.

Leptin receptors in the CNS

• Leptin receptor mRNA and immunoreactivity are also highly expressed in many extra-hypothalamic brain regions including:– hippocampus,– brain stem,– cerebellum, – amygdala and – substantia nigra

Leptin In CNS

• Leptin is thought to enter the brain via two distinct mechanisms. – A saturable transport system is thought to enable

leptin to cross the blood brain barrier via receptor-mediated transcytosis

– Short leptin receptor isoforms, which are capable of binding and internalizing leptin, have been detected on brain microvessels

• In addition,• It appears that leptin is made and released

locally in the CNS. – mRNA and immunoreactivity are widely expressed

throughout the brain– So is it a neurotransmitter???

(Morash et al, 1999;Ur et al, 2002).

What is a neurotransmitter???

• Can be synthesized in the nervous system• Released in the synaptic cleft• Act through post synaptic membrane• Modify postsynaptic membrane potential

Previous studies have demonstrated that leptin inhibits: Peripheral insulin-secreting cells Glucose-responsive hypothalamic neurons and Nucleus tractus solitarius neurons

Via activation of ATP-sensitive potassium (KATP) channels. Similarly leptin inhibits rat hippocampal neurons by Increasing a K+ conductance

It seems Ca2+-activated K+ channels are involved.

Leptin alter synaptic function

• Leptin alter the strength of excitatory synaptic transmission under conditions of enhanced Excitability .– In certain conditions leptin cause hippocampal

long-term depression (LTD)– In contrasts leptin under physiological conditions

(1 mM Mg2+), it promotes the induction of hippocampal long term potentiation (LTP).

Leptin, learning and memory

Recent studies have implicated leptin in associative learning and memory :

leptin-insensitive (db/db mice and fa/fa rats) rodents display impairments in hippocampal long-term potentiation (LTP) and long-term depression (LTD), as well as deficits in spatial memory tasks .

Direct administration of leptin into the hippocampus enhances LTP in vivo.

At the cellular level, leptin converts hippocampal short lasting potentiation (STP) into LTP

Leptin also contributes to synaptic plasticity changes in the hypothalamus as the efficacy of inhibitory and excitatory synaptic transmission is altered in leptin-deficient ob/ob mice

Leptin and Morphological changes

• Leptin increases the number of dendritic filopodia in hippocampal neurons

• Leptin induces actin re-organisation in hippocampal neurons

• Leptin enhances actin-based motility of filopodial extensions

• Leptin promotes formation of functional hippocampal synapses

Blood Brain Barrier

Large interface (100-150 Cm2/kg) between circulation and the brain

Monolayer of endothelial cells Few fenestrations Few Pinocytic vesicles Few transendothelial channels Are joined by tight junctions Continuous basement membrane Astrocytic endfeet Pericytes

Controls penetration of AA, Peptides, proteins,…

Blood-brain barrier (BBB) The BBB constitutes a large interface between the circulation and

the central nervous system (CNS), consisting of: brain and spinal cord.

Its primary component is a monolayer of endothelialcells forming the outer wall of capillaries and venules.

These microvascular endothelial cells have few fenestrations, pinocytic vesicles, or transendothelial channels, and are joined by tight junctions.

A continuous basement membrane, astrocytic endfeet, and pericytes reinforce barrier function from the basolateral side facing the extracellular matrix.

The surface area of the BBB is 100 to 150 cm2/g,. This immense neurovascular interface controls the penetration of

amino acids, peptides, polypeptides, and proteins as well as many other molecules .

Adipokines interact with the BBB

The hypothalamus has an intact BBB . The interactions of adipokines with the BBB can

fall into three categories: changing endothelial function and signaling; Modulating signals from other adipokine and

cytokines; and permeation across the BBB by themselves.

The rich information from leptin provides insights into transcellular transport across the BBB

Physiological regulation of leptin transport

Transport of leptin into brain is reduced by fasting and by genetic mutation and dysfunction of the transporting receptor ObRa .

It is increased by pretreatment with glucose . The saturable transport system for leptin has

been demonstrated both in vivo and in vitro and shows a diurnal rhythm . It is partially saturated in mice with normal

weight being even more so in obese mice .

Leptin receptors ObRa-ObRd

The short isoform of the leptin receptor, ObRa, plays a major role in mediating leptin transport across the BBB.

ObRa has a high level of expression in microvessels and high efficacy in mediating endocytosis in cell systems.

The long isoform, ObRb, contains cytoplasmic domains that interact with the Stats and plays a major role in JAK/Stat signaling.

Nevertheless, ObRa, ObRb, ObRc, and ObRd receptor subtypes can all mediate the binding and endocytosis of leptin in HEK293 cells .

ObRe

• ObRe is the soluble leptin receptor circulating in blood.

• It binds leptin and interferes with ObRb-mediated signaling.

• Recent evidence in vitro and in vivo shows that this soluble receptor for leptin serves as an antagonist not only in the signaling but also in the transport of leptin across endothelial cells .

Profusion of Peripheral Signals

DVC: Dorsal Vagal Complex

Role of leptin in thermogenesis

Physiological effects of LeptinRegulation of food intake ,energy expenditure and body weight .Thermogenesis .Reproductive function .Supresses bone formation .Directly act on the cells of liver and muscles Related to inflammatory response .Contribute to early hemopoiesis.

Role of leptin in reproduction

Fertility influenced by stored body fat

Leptin signals the onset of puberty .

Regulates hypothalamic- pituitary – ovarian function .