The longevity gene INDY (I'm Not Dead Yet) in metabolic control: Potential as pharmacological target

The regulation of metabolic processes by the Indy (Fin Not Dead Yet) (SLC13A5/NaCT) gene was revealed through studies in Drosophila melanogaster and Caenorhabditis elegans. Reducing the expression of Indy in these species extended their life span by a mechanism resembling caloric restriction, without reducing food intake. In D. melanogaster, mutating the Indy gene reduced body fat content, insulin-like proteins and reactive oxygen species production. Subsequent studies indicated that Indy encodes a citrate transporter located on the cell plasma membrane. The transporter is highly expressed in the mammalian liver. We generated a mammalian knock out model deleting the mammalian homolog mIndy (SLC13A5). The knock out animals were protected from HFD induced obesity, fatty liver and insulin resistance. Moreover, we have shown that inducible and liver selective knock down of mIndy protects against the development of fatty liver and insulin resistance and that obese humans with type 2 diabetes and non-alcoholic fatty liver disease have increased levels of mIndy. Therefore, the transporter mINDY (NaCT) has been proposed to be an 'ideal target for the treatment of metabolic disease'. A small molecule inhibitor of the mINDY transporter has been generated, normalizing glucose levels and reducing fatty liver in a model of diet induced obese mice. Taken together, studies from lower organisms, mammals and humans suggest that mINDY (NaCT) is an attractive target for the treatment of metabolic disease

Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus

In addition to tissues such as liver, the plasma membrane sodium-dependent citrate transporter, NaCT (SLC13A5), is highly expressed in brain neurons, but its function is not understood. Loss-of-function mutations in the human SLC13A5 gene have been associated with severe neonatal encephalopathy and pharmacoresistant seizures. The molecular mechanisms of these neurological alterations are not clear. We performed a detailed examination of a Slc13a5 deletion mouse model including video-EEG monitoring, behavioral tests, and electrophysiologic, proteomic, and metabolomic analyses of brain and cerebrospinal fluid. The experiments revealed an increased propensity for epileptic seizures, proepileptogenic neuronal excitability changes in the hippocampus, and significant citrate alterations in the CSF and brain tissue of Slc13a5 deficient mice, which may underlie the neurological abnormalities. These data demonstrate that SLC13A5 is involved in brain citrate regulation and suggest that abnormalities in this regulation can induce seizures. The present study is the first to (i) establish the Slc13a5-knockout mouse model as a helpful tool to study the neuronal functions of NaCT and characterize the molecular mechanisms by which functional deficiency of this citrate transporter causes epilepsy and impairs neuronal function; (ii) evaluate all hypotheses that have previously been suggested on theoretical grounds to explain the neurological phenotype of SLC13A5 mutations; and (iii) indicate that alterations in brain citrate levels result in neuronal network excitability and increased seizure propensity

Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance

Schumann et al. demonstrate that the loss of a lactate transporter Slc16a13 increases mitochondrial respiration in the liver, which reduces hepatic lipid accumulation while increasing hepatic insulin sensitivity in mice fed a high-fat diet. This study suggests SLC16A13 as a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease

The anorexigenic peptide neurotensin relates to insulin sensitivity in obese patients after BPD or RYGB metabolic surgery

Neurotensin is a peptide with effects on appetite and intestinal lipid absorption. Experimental data suggest a role in glucose homeostasis, while human data is missing. Here, 20 morbidly obese subjects either underwent biliopancreatic diversion with duodenal switch (BPD), or Roux-en-Y gastric bypass (RYGB) in a randomized fashion. Before and 1 year after surgery, anthropometric data, body composition, clinical biochemistry, insulin sensitivity by means of euglycemic hyperinsulinemic clamps (HEC) and fasting plasma proneurotensin 1-117 were analyzed. Plasma proneurotensin increased significantly more 1 year after BDP than RYGB (P = 0.028), while weight loss was comparable. After metabolic surgery, proneurotensin correlated positively with insulin sensitivity (M-value) (r = 0.55, P < 0.001), while an inverse relationship with fasting glucose, HOMA-IR and HbA1c was observed (P < 0.05 for all components). After adjustment for age and gender, proneurotensin and BMI remained independently related with delta of M-value (β = 0.46 and β = 0.51, P < 0.05, resp.). From these data we conclude that proneurotensin positively correlates with insulin sensitivity uniquely after weight loss induced by metabolic surgery in humans. BDP leads to a stronger increase in the anorexigenic peptide compared to RYGB