ONTOGENY OF ALTERED THERMOGENESIS IN OBESITY

  • Horwitz, Barbara A (PI)

Project: Research project

Project Details

Description

The amount of energy expended as heat can be a major
determinant of the degree of obesity in man and other animals.
Heat production, in turn, is affected by both genetic and
environmental factors. One major hypothesis to be tested is that
neonatal overnutrition sets the "metabolic stage" for the
development of obesity by altering thermic responses to feeding.
We will examine mechanism(s) underlying altered thermogenesis
in obesity in 2 animal models: genetically lean rats overfed
during suckling (diet-induced obesity) and genetically obese rats
(fa/fa). The first experiments will use 8 day rats to determine if
preobese fa/fa pups show blunted thermic responses to feeding as
they do cold and, if these responses are associated with
alterations in the sympathetic nervous system (as measured by
altered sympathetic input to brown adipose tissue (BAT), the
major site of nonshiverig/nonmuscle regulatory heat production),
or with metabolic alterations in BAT thermogenic pathways, or
with altered monoamine neurotransmitter turnover in the
ventromedial hypothalamus (VMH) and the paraventricular nucleus
(PVN). Parallel studies will be done in genetically lean 8 day rats
overfed during suckling. Such pups show enhanced cold-induced
thermogenesis, but still become obese. Thus, it is imporant to
determine if their thermic response to feeding is blunted; and how
mechanisms associated with their responses differ from those of
genetically obese pups and of lean control pups. The second major
group of experiments will use 10-12 wk obese rats to evaluate
mechanisms underlying the anti-obesity effects of adrenalectomy
(ADX). ADX normalizes BAT thermogenic capacity in genetically
obese rats. It is unclear if this occurs in our diet-induced obese
model. Sympathetic input to BAT and monoamine turnover in the
VMH and PVN will be examined in fa/fa rats and in genetically
lean rats overfed during suckling. Techniques utilized will include
measurements of: oxygen consumption; body composition;
serotonin, dopamine, and their metabolites in selected brain areas
using HPLC (to estimate serotonin and dopamine turnover); brain
and BAT norepinephrine (NE) levels after tyrosine hydroxylase
inhibition (to estimate NE turnover in selected brain areas and
sympathetic input to BAT); BAT succinic dehydrogenase activity;
BAT mitochondrial GDP binding (an in vitro index of BAT
thermogenic capacity); and white adipocyte size and number.
These studies will provide basic information on hormonal and
neural changes associated with (and perhaps resulting in) the
altered thermogenesis accompanying development of obesity in
neonates and adults. They will also help elucidate mechanism(s)
whereby some animals conserve excess calories while others
dissipate them as heat. This understanding will ultimately lead to
more rational strategies for prevention and treatment of human
obesity.
StatusFinished
Effective start/end date4/1/846/30/01

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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