Background - Healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect in response to various vasoconstrictor agonists and this is lost in obesity. A recent study reported that bariatric surgery reverses the damaging effects of obesity on PVAT function. However, PVAT function has not been previously characterised following weight loss induced by caloric restriction, which is often the first line treatment for obesity. This study investigated the mechanisms by which PVAT modulates vascular tone in health and how these are altered in animal models of obesity and diet-induced weight loss. Methods - Male Sprague Dawley rats were fed a 45% fat diet ad libitum for 16 weeks to induce obesity, they were then randomly allocated into two groups; obese rats maintained on the 45% fat diet and weight loss rats that were subjected to 50% caloric restriction for a further four weeks. A weight maintenance group was also established where a cohort of weight loss rats were provided with 70 kcal/day for a further four weeks at the end of the caloric restriction period. A control group was also provided with a 10% fat diet during the 20 week period. The effect of PVAT on the contractility of isolated mesenteric arteries in response to norepinephrine in the presence of pharmacological tools was investigated by wire myography Changes in the PVAT environment were assessed also using western blotting, immunohistochemistry and assays of secretion. Results - PVAT from healthy control rats elicited an anticontractile effect in response to norepinephrine through release of relaxing factors, one of which was nitric oxide. The anticontractile effect was abolished in diet-induced obesity through a mechanism involving local inflammation and reduced nitric oxide bioavailability within PVAT. In addition, reduced KCNQ expression and enhanced COX activation contributed to the loss of anticontractility. Four-week caloric restriction did not restore PVAT anticontractile capacity. However, sustained weight loss led to restoration of PVAT anticontractile function associated with restoration of adipocyte size, reduced inflammation and increased nitric oxide synthase expression. Sustained weight loss and the restoration of PVAT function was associated with reversal of obesity-induced hypertension and normalisation of adipokine levels, including leptin and insulin.Conclusions - Sustained weight loss reverses obesity-induced PVAT damage through a mechanism involving reduced inflammation and reduced nitric oxide bioavailability. Reduced KCNQ activity and enhanced COX activation also contribute to the obesity-associated loss of PVAT anticontractile effect. These data reveal the beneficial effects of weight loss induced by dietary restriction on PVAT function and identify several potential targets for the treatment of PVAT dysfunction associated with obesity.
|Date of Award||1 Aug 2016|
- The University of Manchester
|Supervisor||Gillian Edwards (Supervisor) & Anthony Heagerty (Supervisor)|
- Weight loss
- Perivascular adipose tissue