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Mechanisms by which suppressed thermogenesis in skeletal muscle predispose to insulin resistance and hypertension

English title Mechanisms by which suppressed thermogenesis in skeletal muscle predispose to insulin resistance and hypertension
Applicant Dulloo Abdul G.
Number 102156
Funding scheme Project funding (Div. I-III)
Research institution Département de Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Physiology : other topics
Start/End 01.10.2003 - 30.09.2006
Approved amount 202'938.00
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Lay Summary (English)

Lead
Lay summary
A history of large perturbations in body weight earlier in life - due to malnutrition, disease or unsuccessful slimming - is a risk factor for later development of obesity, type 2 diabetes and hypertension. Such fluctuations in body weight are also associated with an accelerated rate for body fat deposition (i.e. catch-up fat) and resistance to the actions of insulin (insulin resistance) whether during catch-up growth in infancy/childhood or during weight recovery in adults. Our hypothesis is that an efficient ‘energy conserving’ metabolism (i.e. suppressedthermogenesis) - resulting in glucose that is not oxidized in skeletal muscle being diverted for lipid synthesis in adipose tissue - confers to the phase of catch-up growth its sensitivity towards the development of insulin resistance (a state that predisposes to type 2 diabetes and cardiovascular diseases).

Using a validated rat model of weight recovery in which skeletal muscle insulin resistance has been linked to this efficient metabolism for catch-up fat, our research over the past few years have merged techniques of molecular biology, mitochondrial energetics and tissue fatty acid composition analysis to investigate the molecular mechanisms by which the suppression of thermogenesis is brought about, and how these mechanisms of suppressed thermogenesis might crosslink with early development of skeletal muscle insulin resistance

Our studies provide evidence for insulin and leptin resistance in the early phase of catch-up fat, and for impairments in PI3K and AMPK signalling in skeletal muscle, associated with reduced subsarcolemmal mitochondria, in the mechanisms by which suppressed thermogenesis might crosslink with insulin resistance during weight recovery. Consequently, impairments in these signalling pathways, associated with mitochondrial dysfunction, in skeletal muscle may constitute the molecular basis by which the thrifty metabolism (suppressed thermogenesis) that accelerates fat recovery confers enhanced susceptibility to the development of insulin resistance and cardiovascular risks.

The elucidation of early mechanisms that cross-link in the pathogenesis of obesity, diabetes and hypertension will have major implications in the development of strategies for the prevention and treatment of these chronic metabolic diseases - that are major contributors to cardiovascular diseases.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
113634 Mechanisms underlying glucose redistribution from skeletal muscle to adipose tissue during catch-up growth - a determinant for later obesity and metabolic syndrome 01.10.2006 Project funding (Div. I-III)
61687 Role of suppressed skeletal muscle thermogenesis in the patho- genesis of insulin resistance and hypertension 01.10.2000 Project funding (Div. I-III)

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