INDY (I’m Not Dead Yet) is a transporter of TCA cycle intermediates, mediating cellular citrate uptake and is highly expressed in liver and brain. Reduced expression of Indy in lower organisms extended lifespan, reduced whole body fat content and increased mitochondrial biogenesis. In mammals, whole body deletion of the mammalian Indy homolog (mIndy, Slc13a5) increased energy expenditure and protected mice from diet and aging induced obesity and insulin resistance. Here, we address the role of neuronal mIndy in energy homeostasis. We generated a neuronal mIndy knockout (NINKO) mouse model by crossing mIndy-floxed to NestinCre mice. Deletion of mIndy in neurons led to an increase in energy expenditure compared to NestinCre mice after 8 weeks of high fat diet (HFD) feeding (average 24h EE: NestinCre: 11.5±0.5 kcal/h/kg lean mass (lm); NINKO: 13.6±0.6 kcal/h/kg lm; p<0.001). The respiratory exchange ratio decreased from 0.78±0.01 in NestinCre mice to 0.77±0.01 in NINKO mice during the light phase (p<0.001), indicating augmented lipid oxidation in NINKO mice. Body temperature increased in NINKO compared to NestinCre mice (NestinCre: 37.0±0.1°C, NINKO: 37.3±0.1°C at 6pm; p<0.05). Fat mass was reduced and lean mass increased significantly in NINKO mice (NestinCre: 60±1% lm, 31±1% fat mass; NINKO: 63±1% lm, 27±1% fat mass after 8 weeks of HFD feeding; p<0.05). Hyperinsulinemic-euglycemic clamp studies showed improved insulin sensitivity in NINKO mice (steady state GINF NestinCre: 26±2 mg/kg/min; NINKO: 34.6±2 mg/kg/min; p<0.05). Together, these data suggest that neuronal mIndy is a critical regulator of energy and glucose homeostasis in mammals. Further studies will address the mechanisms involved in the effect.


A. Kurzbach: None. D.M. Willmes: None. T. Schumann: None. C. Henke: None. N. El-Agroudy: None. A. Kleinridders: None. A.L. Birkenfeld: None.

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