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Leptin
Exhibits Pluripotent Effects on Appetite and Metabolism. Research documents
Leptin’s critical role in mediating Appetite, Obesity & Metabolic Syndrome
Attributes
In a Nutshell
References
Hunger Urges &
Cravings
The arcuate nucleus (ARC) is a key hypothalamic area for mediating
leptin’s inhibition of food intake. In the ARC are neurons that both
stimulate appetite – through two hormones: neuropeptide Y (NPY) and
agouti-related peptide (AgRP), and inhibit appetite – through proopiomelanocortin (POMC) neurons that activate the appetite
suppressing pathway which includes the satiety hormone α-MSH (alpha
melanocyte-stimulating hormone).
The ventral tegmental area (VTA) contains dopamine neurons that are
important in modulating motivated behavior, addiction and reward. VTA
dopamine neurons express leptin receptors, thus respond to leptin with
activation of an intracellular JAK-STAT pathway and a reduction in firing
rate causing decreased food intake.
In the hippocampus leptin is shown to directly affect the appetite reward
pathway – an example being a reduction in sugar cravings.
(1) Leptin has potent effects on lipid metabolism and acutely increases
glucose metabolism.
(2) Research shows that leptin increases the activation state of key
lipogenic enzymes, such as (1) fatty acid synthase, (2) ATP citrate
lyase, and (3) hormone sensitive lipase (HSL) via the phosphorylation
of the serine residues 563 and 660.
Myers MG, Leibel RL, et al. Obesity and
leptin resistance: distinguishing cause
from effect. Trends Endocrinol Metab.
2010 (Nov); 21(11):643-651.
Appetite
Desires &
Reward
Motivation
Increase in
Thermogenesis
Visceral Fat
Oxidation
Leptin increases the activation state of key lipogenic enzymes, such as:
fatty acid synthase, ATP citrate lyase, and hormone sensitive lipase
(HSL) via the phosphorylation of the serine residues 563 and 660.
Nicotine, Leptin
& Metabolism
Dysfunctional
Hormonal
Signaling
Nicotinic drugs decrease food intake primarily through activation of
POMC neurons and melanocortin pathways.
Insulin
Resistance
(1) Leptin has potent effects on lipid metabolism and acutely increases
glucose metabolism. Thus it is also a strong indicator of insulin levels.
(2) Leptin decreased glucose-stimulated insulin secretion in studies on
islets and β-cells. Leptin improves insulin sensitivity, and decreases
insulin secretion by potentiating hypothalamic leptin and insulin
signaling by stimulating IRS2 phosphorylation.
Leptin
Resistance and
the Yo-Yo
Effect of Dieting
(1) Once the body becomes overweight or obese there is impeded
transport of serum leptin across the blood brain barrier, creating
dysfunctional signaling in areas of the brain expressing leptin mRNA. It
is thought some neural systems that modulate energy balance may
become ‘reset’ to a new and elevated level which would ‘defend’ the
higher level of adiposity or body fat.
(1) Leptin influences the number of both inhibitory and stimulatory
synaptic inputs onto neurons (axonal projections and neurite outgrowth)
within the arcuate nucleus – which is the ‘feeding center’ of the brain.
Obesity creates leptin resistance which impairs leptin-mediated
hippocampal synaptic transmission, thus affecting appetite reward
pathways.
Impaired
Hippocampal
Synaptic
Transmission
The appetite-stimulating hormone NPY has an inhibitory action within
the hypothalamus, where it is released by specific neurons to suppress
GH release. This is done by stimulation of somatostatin release by
alpha 1 and beta-adrenergic receptor-mediated mechanisms.
Hommel JD, Trinko R, Leptin receptor
signaling in midbrain dopamine neurons
regulates feeding. Neuron. 2006
(Sep);51(6):801-810.
(1) Kamohara S, Burcelin R, et al.
Acute stimulation of glucose
metabolism in mice by leptin treatment.
Nature. 1997;389:374-377.
(2) Buettner C, Muse ED, Cheng A. et
al. Leptin controls adipose tissue
lipogenesis via central, STAT3independent mechanisms. Nat Med.
2008; 14(6):667-675.
Buettner C, Muse ED, Cheng A. et al.
Leptin controls adipose tissue
lipogenesis via central, STAT3independent mechanisms. Nat Med.
2008; 14(6):667-675.
Nicotine decrease food intake through
activation of POMC neurons. Science.
2011 (Jun);332(6035):1330.1332.
Rettori V, Milenkovic L, Aguila MC,
McCann SM. Physiologically significant
effect of neuropeptide Y to suppress
growth hormone release by stimulating
somatostatin discharge. Endocrinology.
1990 May;126(5) 2296-2301
(1) Kamohara S, Burcelin R, et al.
Acute stimulation of glucose
metabolism in mice by leptin treatment.
Nature. 1997;389:374-377.
(2) Park SM, Hong SM, et al. Long-term
effects of central leptin and resistin on
body weight, insulin resistance, and βcell function and mass by modulation of
hypothalamic leptin and insulin
signaling. Endocrinology.
2008;149(2):445-454.
(1) Myers Jr MG, Leibel RL, Seeley RJ,
Schwartz MW. Obesity and leptin
resistance: distinguishing cause from
effect. Trends Endocrinol Metab. 2010
Nov; 21(11): 643-651.
(1) Morrison CD, Leptin signaling in
brain: a link between nutrition and
cognition? Biochim Biophys Acta. 2009
May;1972(5):401-408.
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