TRPC6 deficiency causes increased body weight and glucose intolerance in mice fed a normal diet but does not amplify the obesogenic effect of a high fat diet
Authors: Wang Zhen , Jaynes Lance T. , Moak Sydney P. , Dai Xuemei , Fu Yiling , do Carmo Jussara M. , da Silva Alexandre A. , Hall John E. 
Published: April 2020

Transient receptor potential cation channel subfamily C member 6 (TPRC6) is a receptor‐operated cation channel that modulates cell Ca2+ influx. TRPC6 is expressed in many tissues including brain and adipose tissue. We previously showed that whole‐body TRPC6 deletion (TRPC6 KO) causes obesity, impaired glucose tolerance, and leptin resistance in mice fed a standard diet (SD). However, the metabolic consequences of feeding a high fat diet (HFD) to TRPC6 KO mice are still unknown. In this study, we investigated the impact of HFD (45% Cal from fat) from 6 to 18 weeks of age in male and female TRPC6 KO and B6/129s background control mice on body weight (BW), body fat/lean composition, food intake (FI), responses to acute leptin injection, and tolerance to an oral glucose load (OGTT). TRPC6 KO mice of both sexes were heavier than control mice at 6 weeks of age before starting HFD (27.3 ± 1.0 vs 24.2 ± 0.8 g in males and 24.1 ± 0.8 vs 19.1 ± 0.7 in females, n=7/sex, p<0.05). After 10 weeks on HFD, male and female TRPC6 KO mice gained less weight compared to control mice (BW gain: 8.5 ± 0.9 vs 15.2 ± 1.2 g in males and 9.4 ± 0.8 vs 12.2 ± 1.0 g in females from 6 to 16 weeks of age). EchoMRI scans showed that the percentage of lean mass was slightly lower while the percentage of fat mass was higher in TRPC6 KO mice compared to controls at the beginning of HFD. After 10 weeks on HFD, male and female TRPC6 KO mice gained less fat mass than control mice (fat mass gain: 4.2 ± 0.5 vs 11.6 ± 0.6 g in males and 5.7 ± 0.7 vs 8.8 ± 0.6 g in females from 6 to16 weeks of age), while lean mass increased similarly in both genotypes. Daily food intake in TRPC6 KO mice was significantly higher during the first 3 weeks of HDF (average daily FI: 3.5 ± 0.1 vs 2.8 ± 0.1 g in males, and 3.1 ± 0.1 vs 2.6 ± 0.1 in females from 6–8 weeks of age, n=7, p<0.05), after which FI was similar between groups (2.8 ± 0.1 vs 2.7 ± 0.1 g in males and 2.6 ± 0.1 vs 2.4 ± 0.1 in females from 9–16 weeks of age, n=7). After 12 weeks on a HFD, an acute leptin injection (5 mg/kg, i.p.) in fasted mice (n=7/sex/genotype) reduced 24‐hr FI in control mice by 0 % in males and 21% in females. In contrast, leptin reduced 24‐hr FI in TRPC6 KO mice by 15 % in males and 25% in females. An OGTT was performed after 12 weeks on a HFD and male and female TRPC6 KO mice exhibited impaired glucose tolerance compared to control mice (AUC: 19,198 ± 1,357 vs 9,450 ± 2,101 mg/dL × 120 min in males; and 17,117 ± 1,987 vs 5,470 ± 371 mg/dL × 120 min in females, n=7, p<0.05). Our results show that although TRPC6 KO mice have increased adiposity and BW on a SD, they appear to be resistant to HFD‐induced fat mass gain while exhibiting significant intolerance to glucose. Although TRPC6 may play an important role in the regulation of BW, FI, fat mass and glucose handling when fed a SD or HFD, the mechanisms involved in the different metabolic responses in RD and HFD are still unclear and may involve reduced sensitivity to leptin or differential roles of TRPC6 in brain.Support or Funding InformationNHLBI PO1HL51971, NIGMS P20GM104357 and U54GM115428, and NIDDK R00DK113280