Effects of the perinatal environment on the central dopamine system and body weight gain in obesity-prone rats.
which develops as the result of increased energy intake and/or decreased energy
expenditure, has rapidly become one of the largest public health concerns in the world.
The explosive prevalence of the obesity epidemic challenges the notion that a
homeostatic system of energy balance is in complete control of body weight regulation.
The central reward system, particularly the... read moremidbrain dopamine pathways, mediates the
hedonic value of palatable food and may override the homeostatic control of energy
balance. In this work, we use a multi-level approach that includes in vivo microdialysis
and behavioral studies, ex vivo slice electrophysiology measurements of stimulated
dopamine release, and cellular measurements of mRNA and protein expression to study the
influence of dopamine on the development of obesity in inbred obesity-prone (OP) rats.
In female animals that are dietary obese or obesity prone, we show decreases of
approximately 50% in electrically stimulated dopamine release. These significant
deficits in dopamine signaling are linked to decreased sensitivity to amphetamine
injections. In the obesity-prone animals, we have also established deficits in tyrosine
hydroxylase (TH) and vesicular monoamine transporter-2 (VMAT2) mRNA and protein
expression. Obesity-resistant (OR) females that have been exposed to an obesogenic
prenatal environment through embryonic transplantation on day E1 to obesity-prone dames
show similar deficits in central dopamine neurotransmission that are linked to
accelerated body weight gain and decreased spontaneous activity during the pre-pubescent
period. Dopamine replacement in obesity-prone females during this period results in a
decrease of approximately 10% of both food intake and body weight and more than twice as
much stimulated dopamine release in the nucleus accumbens than in obesity-prone control
animals. In conclusion depressed dopamine release can be induced by exposure to an
obesogenic environment during the prenatal period. Sustained deficits in dopamine during
the pre-pubescent period may lead dietary obese and obesity-prone animals to compensate
by overeating, particularly palatable food. Selective targeting to increase the
synthesis and activity of presynaptic regulators of the mesolimbic dopamine system
during this period constitutes a promising approach for both the prevention and
treatment of dietary obesity in offspring that are otherwise prone to developing
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: Emmanuel Pothos.
Committee: Margery Beinfeld, Martin Beinborn, and Efi Kokkotou.
Keyword: Pharmacology.read less