TRPV1-null mice are protected from diet-induced obesity

Abstract

We explored a role for the capsaicin receptor, transient receptor potential channel vanilloid type 1 (TRPV1), in the regulation of feeding and body mass. On a 4.5% fat diet, wild-type and TRPV1-null mice gained equivalent body mass. On an 11% fat diet, however, TRPV1-null mice gained significantly less mass and adiposity; at 44 weeks the mean body weights of wild-type and TRPV1-null mice were approximately 51 and 34g, respectively. Both groups of mice consumed equivalent energy and absorbed similar amounts of lipids. TRPV1-null mice, however, exhibited a significantly greater thermogenic capacity. Interestingly, we found that 3T3-L1 preadipocytes expressed functional calcitonin gene-related peptide receptors. Thus, these data support a potential neurogenic mechanism by which TRPV1-sensitive sensory nerves may regulate energy and fat metabolism.

Figure 1. TRPV1-null mice gain less body mass than wild-type mice on a high-fat diet

(A&B) Mean body mass of wild-type (WT) or TRPV1-null male mice consuming either a low-fat (4.5%) or high-fat (11%) diet from 3 to 25 weeks of age (n=5 for both). (C) Male mice (n=5) switched from a 4.5% fat to an 11% fat diet at 22 weeks of age. (D) Representative photograph of male WT and TRPV1-null mice on an 11% fat diet at 44 weeks of age. (E) Mean body mass of male (age 34 wks: WT n=11, TRPV1-null n=7 and age 44 wks: WT n =4, TRPV1-null n=5) and female (age 40 wks: n=4 for both) mice consuming an 11% fat diet. T-test * P<0.05, **P<0.01, ***P<0.001

Figure 2. TRPV1-null mice have reduced adiposity

(A) Representative photographs of visceral fat in female WT and TRPV1-null mice. (B) Mass of adipose tissue from the abdominal cavity and subcutaneous fat in WT and TRPV1-null mice on an 11% fat diet (n=3, *P<0.05 T-test). (C) Representative cross-sections of gonadal adipose tissue (Hemotoxilyn and Eosin staining, scale bar indicates 200μm) and liver (Oil Red-O staining, scale bar indicates 10μm) from WT and TRPV1-null mice on a high-fat diet. (D) Mean area of hepatocyte lipid droplets (n=300 from 3 WT and 3 TRPV1-null mice; ***P<0.001 T-test).

Figure 3. Wild-type and TRPV1-null mice have the same food intake and intestinal fat absorption but different energy expenditure

(A) Cumulative energy intake of male mice on a 4.5 % fat or 11% fat diet for 8 days (n=4). (B) Mean gain in body mass for WT and TRPV1-null mice after 7 weeks of paired feeding (n=3; *P<0.05, **P<0.01 T-test). (C) Total fat absorption by WT and TRPV1-null mice (n=3). (D) Mean body temperatures of WT (left) and TRPV1-null (right) mice at room temperature (RT) and after one hour at 0–2°C while consuming either the low-fat (4.5% fat) or high-fat (11% fat) diet (WT: 4.5% fat n=7, 11% fat n=6, **P<0.01 ANOVA; TRPV1-null: 4.5% fat n=7, 11% fat n=3, NS by ANOVA).

Figure 4. Mouse 3T3-L1 preadipocytes express functional CGRP receptors

(A) CGRP (50nM) produced Ca²⁺ transients in 3T3-L1 preadipocytes. (B) Adipocytes express mRNA for the CGRP receptor, CRLR. (C&D) Capsaicin (10 μM) failed to produce Ca²⁺ transients in adipocytes, though cells responded to ATP (2 mM).