The role of muscular periarteriolar adipose tissue on vasoreactivity

Obesity is associated with impairment of insulin-mediated glucose uptake,
hypertension and endothelial dysfunction, contributing to cardiovascular risk.
Microvascular dysfunction, characterized by impaired endothelium-dependent
vasodilatation and impaired effects of insulin on microvascular function, plays
an important role in the pathogenesis of the metabolic syndrome.
Insulin-mediated glucose uptake occurs primarily in muscle, and depends not
only on the rate of uptake by myocytes, but also on the rate of delivery of
glucose and insulin via the microcirculation. Under physiological conditions,
an increase in insulin has both vasodilator (via NO synthesis) and
vasoconstrictor (via endothelin-I synthesis) effects on muscle resistance
arteries, with a net result of increased microvascular perfusion. In obesity,
however, the vasodilator effects have been shown to be impaired, thereby
limiting the ability of insulin to increase substrate access to muscle. The
causes of this impaired insulin-mediated blood flow in obesity are, however,
not clear. Insulin*s effects in (vascular) cells are mediated via a complex
signalling cascade (figure), and impaired activation of this cascade in
vascular cells has been demonstrated and likely contributes to the perturbation
of insulin*s effects on vasoreactivity.
Expression of TNF-α is increased in the adipose tissue of obese humans and
animals. Insulin induces vasoconstriction of skeletal muscle resistance
arterioles in the presence of TNF-α by inhibition of the vasodilator pathway at
the level of Akt. However, levels of TNF-α are primarily higher in adipose
tissue than in the systemic circulation, suggesting local production of TNF-α
is necessary in order to influence vasoreactivity.
A previously undiscovered type of fat was described recently. This adipose
tissue is called muscle periarteriolar adipose tissue (mPAT), and is located
around the origin of the arteriole. We hypothesize that mPAT may be able to
influence vasoreactivity of the arteriole, thereby affecting delivery of
nutrients and other substances to the vascular tree. mPAT may exert these
effects by influencing the insulin signalling-cascade through the production of
adipokines, such as TNF-α.

This study aims to determine whether obesity and/or other metabolic syndrome
markers are associated with accumulation of mPAT with an inflammatory
phenotype, whether the mPAT phenotype differs from subcutaneous and visceral
adipose tissue, and whether this mPAT disturbs insulin-mediated vasoreactivity.
We further hypothesize that mPAT produces adipokines that inhibit
insulin-mediated vasodilatation.

This project should be performed, because mPAT is a previously unstudied type
of adipose tissue. The role of mPAT in the pathophysiology of insulin
resistance is potentially important.

1. Does mPAT directly impair vasoreactivity to insulin and acetylcholine ex
vivo in arterioles obtained from muscle biopsy in lean and obese individuals?
2. Is obesity in humans associated with the accumulation of mPAT and an
inflammatory mPAT phenotype?
3. Is this human mPAT quantitatively and/or qualitatively associated with an
impaired muscle blood flow response to hyperinsulinemia, as assessed by
Contrast Enhanced UltraSonography (CEUS)?

This study is conducted as a case control study. The setting is outpatient
based, with three visits to the clinical research unit at the VUmc. The first
visit will take approximately one-and-a-half hours, the second visit 5 hours
and the third will take approximately 1 hour.

Subjects will visit the clinical research unit three times after an overnight
fast, the first time to undergo a detailed medical history, physical
examination and blood sampling, the second time to undergo hyperinsulinemic
euglycemic clamping, and contrast enhanced ultrasonography, as well as
iontophoresis and laser Doppler, and the third time a biopsy of the quadriceps
muscle will be performed under local anaesthesia. Risks associated with
participation consist of (not necessarily) myalgia and bleeding after biopsy,
as well as small risks of hypoglycaemia or hyperglycaemia during
hyperinsulinemic euglycemic clamping, and headache, flushing and back pain
during contrast enhanced ultrasonography. Bruising and local pain in the
antecubital fold may be experienced during and after placement of venous
catheters and/or during blood sampling.
Subjects will receive ¤250 after completion of the protocol.
The groups are chosen because of their high likelihood to express different
amounts and phenotypes of mPAT.