Effects of Leptin on Exercise Effects of Leptin on Exercise and Health in Humanand Health in Human

Human LeptinHuman Leptin

A protein of 167 A protein of 167 amino acidsamino acids. .

A molecular weight of 16 kDa, A molecular weight of 16 kDa, peptide peptide hormonehormone secreted by secreted by adipose tissueadipose tissue. .

the level in circulation is directly proportional the level in circulation is directly proportional to the total amount of to the total amount of fatfat in the body. in the body.

regulates body weight and energy homeostasis regulates body weight and energy homeostasis via its actions on specific via its actions on specific hypothalamic nucleihypothalamic nuclei

BiosynthesisBiosynthesisthe major source of leptin:the major source of leptin:– brown adipose tissue, brown adipose tissue, – placenta (syncytiotrophoblasts),placenta (syncytiotrophoblasts),– ovaries, skeletal muscle, ovaries, skeletal muscle, – stomach (lower part of fundic glands), stomach (lower part of fundic glands), – mammary epithelial cells, mammary epithelial cells, – bone marrow, bone marrow, – PituitaryPituitary– and liverand liver

Leptin has also been discovered to be synthesised Leptin has also been discovered to be synthesised from gastric chief cells and P/D1 cells in the stomachfrom gastric chief cells and P/D1 cells in the stomach

Leptin Production and AdipocyteLeptin Production and Adipocyte

BiosynthesisBiosynthesis

Leptin is the product of the obese (Leptin is the product of the obese (obob) gene ) gene that is synthesized predominantly, although that is synthesized predominantly, although not exclusively, by not exclusively, by white adipose tissuewhite adipose tissue

The The Ob(Lep)Ob(Lep) gene (Ob for obese, Lep for gene (Ob for obese, Lep for leptin) is located on leptin) is located on chromosome 7chromosome 7 (q31.31- (q31.31-q32.1) in humans. q32.1) in humans.

FunctionFunction

Leptin acts on receptors in the hypothalamus of Leptin acts on receptors in the hypothalamus of the brain where it inhibits appetite by the brain where it inhibits appetite by – (1) counteracting the effects of neuropeptide Y (a (1) counteracting the effects of neuropeptide Y (a

potent feeding stimulant secreted by cells in the gut potent feeding stimulant secreted by cells in the gut and in the hypothalamus);and in the hypothalamus);

– (2) counteracting the effects of anandamide (another (2) counteracting the effects of anandamide (another potent feeding stimulant that binds to the same potent feeding stimulant that binds to the same receptors as THC, the primary active ingredient of receptors as THC, the primary active ingredient of marijuana); marijuana);

– (3) promoting the synthesis of α-MSH, an appetite (3) promoting the synthesis of α-MSH, an appetite suppressantsuppressant

SatietySatiety

Leptin binds to neuropeptide Y (NPY) neurons Leptin binds to neuropeptide Y (NPY) neurons in the arcuate nucleus, in such a way that in the arcuate nucleus, in such a way that decreases the activity of these neurons. decreases the activity of these neurons.

Leptin signals to the brain that the body has Leptin signals to the brain that the body has had enough to eat, producing a feeling of had enough to eat, producing a feeling of satietysatiety

Regulation of satiety signals Regulation of satiety signals

Model for regulation of the hindbrain response Model for regulation of the hindbrain response to satiety signals by hormonal input from the to satiety signals by hormonal input from the ARC. ARC. Adiposity signals such as insulin and leptin Adiposity signals such as insulin and leptin circulate in proportion to body fat mass and circulate in proportion to body fat mass and act on hypothalamic ARC neurons that project act on hypothalamic ARC neurons that project to hypothalamic areas such as the PVNto hypothalamic areas such as the PVNthese “second order” neurons project to these “second order” neurons project to hindbrain autonomic centers such as the NTS hindbrain autonomic centers such as the NTS that process afferent input from satiety signals that process afferent input from satiety signals such as CCK. such as CCK.

Input from descending, leptin-sensitive Input from descending, leptin-sensitive hypothalamic projections is integrated in the hypothalamic projections is integrated in the NTS with vagally mediated input from CCK, NTS with vagally mediated input from CCK, such that the timing of meal termination is such that the timing of meal termination is regulated by changes in body fat contentregulated by changes in body fat content

Interaction with amylinInteraction with amylin

Co-administration of two neurohormones Co-administration of two neurohormones known to have a role in body weight control, known to have a role in body weight control, amylin (produced by beta cells in the amylin (produced by beta cells in the pancreas) and leptin (produced by fat cells), pancreas) and leptin (produced by fat cells), results in sustained, fat-specific weight loss in results in sustained, fat-specific weight loss in a leptin-resistant animal model of obesitya leptin-resistant animal model of obesity

Leptin and ObesityLeptin and Obesity

obese individuals generally obese individuals generally exhibit an unusually high exhibit an unusually high circulating concentration of circulating concentration of leptinleptin

the high sustained the high sustained concentrations of leptin from concentrations of leptin from the enlarged adipose stores the enlarged adipose stores result in leptin desensitizationresult in leptin desensitization

The pathway of leptin control The pathway of leptin control in obese people doesn't in obese people doesn't adequately receive the satiety adequately receive the satiety feeling subsequent to eatingfeeling subsequent to eating

As it circulates through the As it circulates through the cerebrovasculaturecerebrovasculature, transporters for leptin , transporters for leptin carry it across the BBB to enter the interstitial carry it across the BBB to enter the interstitial fluid of the brain fluid of the brain

Leptin functions are thought to occur through Leptin functions are thought to occur through the leptinthe leptin receptors mainly in the hypothalamic receptors mainly in the hypothalamic nuclei nuclei

Model of leptin regulation of NPY/GABA and POMC neurons in the ARC

FunctionFunctionLeptin acts on receptors in the hypothalamus of Leptin acts on receptors in the hypothalamus of the brain where it inhibits appetite by the brain where it inhibits appetite by – (1) counteracting the effects of (1) counteracting the effects of neuropeptideneuropeptide YY(a (a

potent feeding stimulant secreted by cells in the gut potent feeding stimulant secreted by cells in the gut and in the hypothalamus); and in the hypothalamus);

– (2) counteracting the effects of (2) counteracting the effects of anandamideanandamide (another (another potent feeding stimulant that binds to the same potent feeding stimulant that binds to the same receptors as THC, the primary active ingredient of receptors as THC, the primary active ingredient of marijuana); marijuana);

– (3) promoting the synthesis of α-MSH, an appetite (3) promoting the synthesis of α-MSH, an appetite suppressant suppressant

This inhibition is long-term, in contrast to the This inhibition is long-term, in contrast to the rapid inhibition of eating by rapid inhibition of eating by cholecystokinin cholecystokinin (CCK) and the slower suppression of hunger (CCK) and the slower suppression of hunger between meals mediated by between meals mediated by PYY3-36PYY3-36. .

Peptide YY3-36 (PYY3-36), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal

Presynaptic InhibitionPresynaptic Inhibition

The absence of leptin (or its receptor) leads to The absence of leptin (or its receptor) leads to uncontrolled food intake and resulting obesity.uncontrolled food intake and resulting obesity.

Several studies have shown that fasting or Several studies have shown that fasting or following a very-low-calorie diet (VLCD) following a very-low-calorie diet (VLCD) lowers leptin levelslowers leptin levels

Dynamics of leptin due to an acute change in Dynamics of leptin due to an acute change in energy balance are related to appetite and energy balance are related to appetite and eventually to food intake eventually to food intake

Two neurohormones known to have a role in Two neurohormones known to have a role in body weight control, amylin (produced by beta body weight control, amylin (produced by beta cells in the pancreas) and leptin (produced by cells in the pancreas) and leptin (produced by fat cells), fat cells),

Resting leptin responses to acute and chronic Resting leptin responses to acute and chronic resistance training in type 2 diabetic men and resistance training in type 2 diabetic men and

womenwomen. . Kanaley JA, Fenicchia LM, Miller CS, Ploutz-Synder LL, Weinstock RS, Carhart R, Azevedo JL Jr.Int J Obes Relat Metab Disord. Kanaley JA, Fenicchia LM, Miller CS, Ploutz-Synder LL, Weinstock RS, Carhart R, Azevedo JL Jr.Int J Obes Relat Metab Disord.

2001 Oct;25(10):1474-80.2001 Oct;25(10):1474-80.

17 controls and 13 type 2, obese diabetics, age 17 controls and 13 type 2, obese diabetics, age 40-55 y 40-55 y resting blood samples drawn at 08:00 h (12 h resting blood samples drawn at 08:00 h (12 h postprandial) at the beginning of the study postprandial) at the beginning of the study (pre-training)(pre-training) 24 h after a three repetition maximal weight 24 h after a three repetition maximal weight lifting bout (acute) and 72 h after their last lifting bout (acute) and 72 h after their last training bout of 6 weeks of resistance training training bout of 6 weeks of resistance training (chronic)(chronic)

Serum leptin concentrations were significantly Serum leptin concentrations were significantly higher in the type 2 diabetics than in the higher in the type 2 diabetics than in the control group at pre-training control group at pre-training

Compared to pre-training, the leptin levels Compared to pre-training, the leptin levels decreased after acute exercise in the diabetics decreased after acute exercise in the diabetics but not in the control subjectsbut not in the control subjects

The decreased resting leptin concentrations The decreased resting leptin concentrations approximately 24 h post-acute exercise may be approximately 24 h post-acute exercise may be due to reduced glucose availability to the due to reduced glucose availability to the adipose tissueadipose tissue

Ten men completed an acute heavy-resistance Ten men completed an acute heavy-resistance exercise protocol (AHREP;50 total sets comprised of exercise protocol (AHREP;50 total sets comprised of the squat, bench press, leg press, and lat pull-down) the squat, bench press, leg press, and lat pull-down) from 1500 to 1700 h. from 1500 to 1700 h. Blood was sampled hourly postexercise until 0600 h Blood was sampled hourly postexercise until 0600 h the next morning and also during a time-matched the next morning and also during a time-matched control period. control period. Leptin concentrations were measured by an Leptin concentrations were measured by an immunoradiometric assay. immunoradiometric assay. Resting energy expenditure (REE) was measured via Resting energy expenditure (REE) was measured via indirect calorimetry using a ventilated hood indirect calorimetry using a ventilated hood beginning approximately 0600 h after both overnight beginning approximately 0600 h after both overnight conditions.conditions.

Leptin concentrations experience a delayed Leptin concentrations experience a delayed reduction after resistance exercise in men.reduction after resistance exercise in men.

Nindl BC, Kraemer WJ, Arciero PJ, Samatallee N, Leone CD, Mayo MF, Hafeman DNindl BC, Kraemer WJ, Arciero PJ, Samatallee N, Leone CD, Mayo MF, Hafeman D

The estimated caloric expenditure from the The estimated caloric expenditure from the AHREP was 856 +/- 114 kcal. AHREP was 856 +/- 114 kcal. No differences between the control and No differences between the control and exercise conditions were observed for serum exercise conditions were observed for serum leptin concentrations until 9 h postexercise.leptin concentrations until 9 h postexercise. Significant interaction effects indicated lower Significant interaction effects indicated lower serum leptin concentrations postexercise at serum leptin concentrations postexercise at hours 9, 10, 12 , and 13 .hours 9, 10, 12 , and 13 .This delayed reduction was accompanied by a This delayed reduction was accompanied by a 12% elevation in morning-after REE12% elevation in morning-after REE

Leptin concentrations experience a delayed Leptin concentrations experience a delayed ( approximately 9 h) reduction in the systemic ( approximately 9 h) reduction in the systemic circulation after acute resistance exercise. This circulation after acute resistance exercise. This decline is likely associated with the disruption decline is likely associated with the disruption in metabolic homeostasis created by the high-in metabolic homeostasis created by the high-intensity, long-duration, energy expenditureintensity, long-duration, energy expenditure

SummarySummary

Leptin circulates at levels proportional to body Leptin circulates at levels proportional to body fat.fat.It enters the central nervous system (CNS) in It enters the central nervous system (CNS) in proportion to its plasma concentration.proportion to its plasma concentration.Its receptors are found in brain neurons Its receptors are found in brain neurons involved in regulating energy intake and involved in regulating energy intake and expenditure.expenditure.It controls food intake and energy expenditure It controls food intake and energy expenditure by acting on receptors in the mediobasal by acting on receptors in the mediobasal hypothalamushypothalamus

Response of leptin to muscular exercise. Response of leptin to muscular exercise. Physical exercise and or training can reduce Physical exercise and or training can reduce fat mass fat mass Changes in energy expenditure and affect Changes in energy expenditure and affect hormonal concentrations (insulin, cortisol, hormonal concentrations (insulin, cortisol, growth hormone, catecholamines, testosterone growth hormone, catecholamines, testosterone etc.) and etc.) and metabolites (free fatty acids, lactic acid, metabolites (free fatty acids, lactic acid, triglycerides etc.).triglycerides etc.).

DiscussionDiscussion

What is your thinking about the relation What is your thinking about the relation between the human leptin and athletic between the human leptin and athletic performance?performance?

Could you draw a diagram to denote the Could you draw a diagram to denote the leptid’s effect on POMC/CART and leptid’s effect on POMC/CART and NPY/AgRP and Arcuate nucleus to change an NPY/AgRP and Arcuate nucleus to change an eating behavior.eating behavior.

gut peptide cholecystokinin (CCK)

hypothalamic arcuate nucleus (ARC) a key forebrain site of leptin action

agouti-related peptide (AgRP),

α-melanocyte-stimulating hormone (α-MSH).

Pro-opiomelanocortin (POMC)Cocaine-and amphetamine-regulating transcrip (CART)Ghrelin, a hormone secreted when stomach is emptyPeptide YY 3-36 (PYY3-36) is produced by the gut and is released into the circulation in response to food ingestion Y2R agonist is peptide YY3 36 (PYY3 36),