Nonalcoholic fatty liver disease (NAFLD) is becoming the most common liver disorder worldwide. Specifically, nonalcoholic steatohepatitis (NASH) and fibrosis pose an enormous burden for patients and health-care systems. In the absence of approved pharmacological therapies, effective lifestyle interventions for NAFLD, such as dietary strategies and exercise training, are currently the therapeutic strategies of choice. This review covers the influence of macronutrient quality and quantity (i.e., low-carbohydrate and high-protein diets), for successful reduction of intrahepatocellular lipids (IHL). Moreover, we discuss the effectiveness of different modalities of physical exercising with and without weight loss. These lifestyle modifications not only provide strategies to reduce IHL but may also hold a still underestimated potential to induce improvement and/or even remission of NAFLD. Nonalcoholic Fatty Liver Disease: The ChallengeThe global burden of nonalcoholic fatty liver disease (NAFLD) (see Glossary), which ranges from steatosis to nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma, is rapidly rising [1]. Recent data reveal a world-wide prevalence of 24% among the adult population [2]. The etiology is multifactorial and yet incompletely understood, but involves accumulation of intrahepatic lipids (IHL), alterations of energy metabolism, insulin resistance, and inflammatory processes [3]. Besides genetic predisposition, unhealthy dietary habits and low levels of physical activity and regular exercising are the main modifiable risk factors for NAFLD. In the absence of approved pharmacological agents for the treatment of NAFLD, the current European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) Clinical Practice Guidelines for the management of NAFLD recommend lifestyle modification as the strategy of choice for preventing and improving NALFD [1]. They suggest to induce an energy deficit of 500-1000 kcal, leading to an associated weight loss of 7-10% by low-to-moderate fat, low-carbohydrate ketogenic or high-protein diets, and moderate-intensity aerobic exercise training with additional resistance training [1]. However, while there is clear evidence that weight loss improves IHL, only few people achieve the required 10% minimum weight loss required for clinically meaningful improvement or resolution of NASH and fibrosis [4]. Here, we discuss the recent evidence supporting or challenging this view.Is Nutritional Quality or Quantity More Important to Reduce IHL? Effect of Body Weight ReductionA surplus of 1000 kcal for 12 weeks in obese people, leading to a weight gain of 6% body weight, increases IHL by $50%, mainly through increased de novo lipogenesis together with reduced intrahepatic fatty acid oxidation [5], while fatty acid availability is less relevant in this setting [6,7]. Moreover, a single oral saturated fat load increases IHL, reduces hepatic insulin sensitivity in ...

The regulation of metabolic processes by the Indy (I'm 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.

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Reduced expression of the plasma membrane citrate transporter INDY (acronym I’m Not Dead, Yet ) extends life span in lower organisms. Deletion of the mammalian Indy ( mIndy ) gene in rodents improves metabolism via mechanisms akin to caloric restriction, known to lower blood pressure (BP) by sympathoadrenal inhibition. We hypothesized that mIndy deletion attenuates sympathoadrenal support of BP. Continuous arterial BP and heart rate (HR) were reduced in mINDY-KO mice. Concomitantly, urinary catecholamine content was lower, and the decreases in BP and HR by mIndy deletion were attenuated after autonomic ganglionic blockade. Catecholamine biosynthesis pathways were reduced in mINDY-KO adrenals using unbiased microarray analysis. Citrate, the main mINDY substrate, increased catecholamine content in pheochromocytoma cells, while pharmacological inhibition of citrate uptake blunted the effect. Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis. Deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.

Retinal hypoxia triggers abnormal vessel growth and microvascular hyper‐permeability in ischemic retinopathies. Whereas vascular endothelial growth factor A (VEGF‐A) inhibitors significantly hinder disease progression, their benefits to retinal neurons remain poorly understood. Similar to humans, oxygen‐induced retinopathy (OIR) mice exhibit severe retinal microvascular malformations and profound neuronal dysfunction. OIR mice are thus a phenocopy of human retinopathy of prematurity, and a proxy for investigating advanced stages of proliferative diabetic retinopathy. Hence, the OIR model offers an excellent platform for assessing morpho‐functional responses of the ischemic retina to anti‐angiogenic therapies. Using this model, we investigated the retinal responses to VEGF‐Trap (Aflibercept), an anti‐angiogenic agent recognizing ligands of VEGF receptors 1 and 2 that possesses regulatory approval for the treatment of neovascular age‐related macular degeneration, macular edema secondary to retinal vein occlusion and diabetic macular edema. Our results indicate that Aflibercept not only reduces the severity of retinal microvascular aberrations but also significantly improves neuroretinal function. Aflibercept administration significantly enhanced light‐responsiveness, as revealed by electroretinographic examinations, and led to increased numbers of dopaminergic amacrine cells. Additionally, retinal transcriptional profiling revealed the concerted regulation of both angiogenic and neuronal targets, including transcripts encoding subunits of transmitter receptors relevant to amacrine cell function. Thus, Aflibercept represents a promising therapeutic alternative for the treatment of further progressive ischemic retinal neurovasculopathies beyond the set of disease conditions for which it has regulatory approval. Cover Image for this issue: doi: .

Genome-wide association studies have identified SLC16A13 as a novel susceptibility gene for type 2 diabetes. The SLC16A13 gene encodes SLC16A13/MCT13, a member of the solute carrier 16 family of monocarboxylate transporters. Despite its potential importance to diabetes development, the physiological function of SLC16A13 is unknown. Here, we validate Slc16a13 as a lactate transporter expressed at the plasma membrane and report on the effect of Slc16a13 deletion in a mouse model. We show that Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice. We propose a mechanism for improved hepatic insulin sensitivity in the context of Slc16a13 deficiency in which reduced intrahepatocellular lactate availability drives increased AMPK activation and increased mitochondrial respiration, while reducing hepatic lipid content. Slc16a13 deficiency thereby attenuates hepatic diacylglycerol-PKCε mediated insulin resistance in obese mice. Together, these data suggest that SLC16A13 is a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease.

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.

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