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ENERGY BALANCE. S. Zahedi Endocrine Research Center Research Institute for Endocrine Sciences Shaheed Beheshti University of Medical Sciences 2 nd obesity Congress 29-30- Oct. 2009 Tehran-Iran.

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energy balance

ENERGY BALANCE

S. Zahedi

Endocrine Research Center

Research Institute for Endocrine Sciences

ShaheedBeheshti University of Medical Sciences

2nd obesity Congress

29-30- Oct. 2009

Tehran-Iran

slide3
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

slide4
Genes

Susceptibility genes

(many genes, each with small effect)

Monogenic syndromes

OBESITY

ENERGY BALANCE

Physical activity

Food intake

Environment/Lifestyle

slide5
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.

slide6
Nervous

Control systems in the body

Hormonal

feeding experiments
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
slide8
Brain Lesioning Studies
  • Profound obesity from destruction of hypothalamic:
    • Paraventricular nucleus (PVN)
    • Ventromedial nucleus (VMN)
    • Dorsomedial nucleus (DMN)
  • Anorexia/weight loss from destruction of:
    • Lateral hypothalamic area (LHA)
slide9
Brain Centers in Energy Homeostasis

NPY

AgRP

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

phases of food in gi tract
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
Food intake control stages
  • Very short term
  • Short term
  • Long term
food intake control stages1
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)
slide17
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
slide18
Appetite is

suppressed

CNS

MSH

from POMC neurons

Periphery

Metabolic activity increases to burn fat

Leptin

+

Hypothalamus

arcuate nucleus

JAK-STAT3

Leptin

receptor

Adipose

Adipose stores

are HIGH

slide19
Appetite is

enhanced

JAK-STAT3

CNS

Periphery

Metabolic activity decreases limiting fat burning

Leptin

+

Leptin

receptor

Hypothalamus

 AGRP from hunger neurons

Block MSH binding

MSH

Adipose

Adipose stores

are low

conclusion
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.!!!!!!!!!!!!!!!
slide28
Profusion of Peripheral Signals

DVC: Dorsal Vagal Complex

slide35
Dopamine and Outputs to Striatum

(motor activity)

(motivation/reward)

SNPC: substantia nigra pars compacta

VTA: ventral tegmental area

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.

slide37
Bias Toward Weight Gain

Arc destruction causes weight gain.

Response to weight loss bidirectional; weight gain unidirectional.

DMc4r=> weight gain whereas Dnpy=>no weight loss.

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

HOWEVER:

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

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

slide38
Currently Approved Therapies

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

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

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

4. Rimonabant (Acomplia; CR1 endocannabinoid antagonsist).

adipokines
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
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 cns1
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 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
slide43
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
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
slide45
Previous studies have demonstrated that leptin inhibits:
    • Peripheral insulin-secreting cells
    • Glucose-responsive hypothalamic neurons and
    • Nucleus tractussolitarius 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 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
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 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
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
      • Astrocyticendfeet
      • Pericytes
  • Controls penetration of AA, Peptides, proteins,…
blood brain barrier bbb
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 endothelialcellsforming 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, astrocyticendfeet, 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
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 leptinprovides insights into transcellular transport across the BBB
physiological regulation of leptin transport
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
Leptin receptors ObRa-ObRd
  • The short isoform of the leptin receptor, ObRa, plays a major role in mediating leptintransport across the BBB.
  • ObRahas a high level of expression in microvessels and high efficacy in mediating endocytosis in cell systems.
  • The long isoform, ObRb, contains cytoplasmicdomains 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 .
slide54
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 .
slide55
Profusion of Peripheral Signals

DVC: Dorsal Vagal Complex

physiological effects of leptin
Physiological effects of Leptin
  • Regulation 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
Role of leptin in reproduction
  • Fertility influenced by stored body fat
  • Leptin signals the onset of puberty .
  • Regulates hypothalamic- pituitary – ovarian function .
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