A Role for TRPV1 in Influencing the Onset of Cardiovascular Disease in Obesity

Abstract

Obesity induced by Western diets is associated with type 2 diabetes mellitus and cardiovascular diseases, although underlying mechanisms are unclear. We investigated a murine model of diet-induced obesity to determine the effect of transient potential receptor vanilloid 1 (TRPV1) deletion on hypertension and metabolic syndrome. Wild-type and TRPV1 knockout mice were fed normal or high-fat diet from 3 to 15 weeks. High-fat diet-fed mice from both genotypes became obese, with similar increases in body and adipose tissue weights. High-fat diet-fed TRPV1 knockout mice showed significantly improved handling of glucose compared with high-fat diet-fed wild-type mice. Hypertension, vascular hypertrophy, and altered nociception were observed in high-fat diet-fed wild-type but not high-fat diet-fed TRPV1 knockout mice. Wild-type, but not high-fat diet-fed TRPV1 knockout, mice demonstrated remodeling in terms of aortic vascular hypertrophy and increased heart and kidney weight, although resistance vessel responses were similar in each. Moreover, the wild-type mice had significantly increased plasma levels of leptin, interleukin 10 and interleukin 1β, whereas samples from TRPV1 knockout mice did not show significant increases. Our results do not support the concept that TRPV1 plays a major role in influencing weight gain. However, we identified a role of TRPV1 in the deleterious effects observed with high-fat feeding in terms of inducing hypertension, impairing thermal nociception sensitivity, and reducing glucose tolerance. The observation of raised levels of adipokines in wild-type but not TRPV1 knockout mice is in keeping with TRPV1 involvement in stimulating the proinflammatory network that is central to obesity-induced hypertension and sensory neuronal dysfunction.

Tail‐Cuff Technique and Its Influence on Central Blood Pressure in the Mouse

“…The catheter was secured using surgical braided silk (5.0, waxed sutures, Pearsalls Ltd, UK) and the transmitter was placed subcutaneously in the right flank. The abdominal wall and the skin incision were sutured separately using absorbable sutures (Vicryl 5.0; Ethicon, Johnson & Johnson) 29. For measurement of temperature, the transmitter (TA10TA‐F10; DSI) was inserted.…”

Cannabinoid 1 and Transient Receptor Potential Vanilloid 1 Receptors Discretely Modulate Evoked Glutamate Separately from Spontaneous Glutamate Transmission

“…Male Sprague Dawley rats (150 -250 g; Charles River) were used. Brains were removed under deep isoflurane anesthesia (5%), and hindbrain slices were prepared as described previously (Doyle and Andresen, 2001). Briefly, a wedge of ventral brainstem was removed to tilt the hindbrain so that horizontal slices (250 m) contained the ST in the same plane as cell bodies in the caudal NTS (VT-1000S vibrating microtome from Leica; and sapphire blade from Delaware Diamond Knives).…”

“…The latency was measured from the stimulus shock to the onset of the first EPSC evoked in each burst, and the jitter was then calculated as SD of the latency and averaged across Ն30 ST shocks. These low-jitter (Ͻ200 s), consistent-waveform EPSCs were selected for study as a monosynaptic unitary ST afferent input (Doyle and Andresen, 2001;Bailey et al, 2006a). Capsaicin (CAP; 100 nM) tests were conducted at the end of each experiment to verify vanilloidsensitive (TRPV1 ϩ ) or vanilloid-insensitive (TRPV1 Ϫ ) afferents (Doyle and Andresen, 2001;Bailey et al, 2006a;.…”

“…Second-order solitary tract nucleus (NTS) neurons receive solitary tract (ST) afferent inputs that either express transient receptor potential vanilloid 1 (TRPV1 ϩ ) or do not (TRPV1 Ϫ ; Doyle et al, 2002;Jin et al, 2004;Laaris and Weinreich, 2007). Shocks to the ST activate afferent axons that trigger synchronous release of glutamate [ST-evoked EPSCs (eEPSCs)], a process that is indistinguishable between TRPV1 ϩ and TRPV1 Ϫ afferents (Bailey et al, 2006b;Andresen and Peters, 2008).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…A recent study found no difference in weight gain between TRPV1 knockout and wild-type mice kept on a high-fat diet (Marshall et al, 2013). These seemingly contradictory findings may be reconciled by a recent study in which the phenotype of TRPV1 knockout mouse was 1) dependent on the age of the animals and 2) was also heavily influenced by environmental variables (diet, room temperature, etc) that can impact thermoregulation (Wanner et al, 2011).…”