SUMMARY Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.

Mitochondrial dysfunction has been implicated in the development of insulin resistance (IR); however, a large variety of association and intervention studies as well as genetic manipulations in rodents have reported contrasting results. Indeed, even 39 years after the first publication describing a relationship between IR and diminished mitochondrial function, it is still unclear whether a direct relationship exists, and more importantly if changes in mitochondrial capacity are a cause or consequence of IR. This review will take a journey through the past and summarise the debate about the occurrence of mitochondrial dysfunction and its possible role in causing decreased insulin action in obesity and type 2 diabetes. Evidence is presented from studies in various human populations, as well as rodents with genetic manipulations of pathways known to affect mitochondrial function and insulin action. Finally, we have discussed whether mitochondria are a potential target for the treatment of IR.

Aims/hypothesis Metabolic disorders are commonly investigated using knockout and transgenic mouse models. A variety of mouse strains have been used for this purpose. However, mouse strains can differ in their inherent propensities to develop metabolic disease, which may affect the experimental outcomes of metabolic studies. We have investigated straindependent differences in the susceptibility to diet-induced obesity and insulin resistance in five commonly used inbred mouse strains (C57BL/6J, 129X1/SvJ, BALB/c, DBA/2 and FVB/N). Methods Mice were fed either a low-fat or a high-fat diet (HFD) for 8 weeks. Whole-body energy expenditure and body composition were then determined. Tissues were used to measure markers of mitochondrial metabolism, inflammation, oxidative stress and lipid accumulation. Results BL6, 129X1, DBA/2 and FVB/N mice were all susceptible to varying degrees to HFD-induced obesity, glucose intolerance and insulin resistance, but BALB/c mice exhibited some protection from these detrimental effects. This protection could not be explained by differences in mitochondrial metabolism or oxidative stress in liver or muscle, or inflammation in adipose tissue. Interestingly, in contrast with the other strains, BALB/c mice did not accumulate excess lipid (triacylglycerols and diacylglycerols) in the liver; this is potentially related to lower fatty acid uptake rather than differences in lipogenesis or lipid oxidation. Conclusions/interpretation Collectively, our findings indicate that most mouse strains develop metabolic defects on an HFD. However, there are inherent differences between strains, and thus the genetic background needs to be considered carefully in metabolic studies. Keywords

The liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of advanced mass spectrometry “omics” approaches and detailed experimentation in cells, mice, and humans, we now understand that the liver secretes a wide array of proteins, metabolites, and noncoding RNAs (miRNAs) and that many of these secreted factors exert powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving field of “hepatokine” biology with a particular focus on delineating previously unappreciated communication between the liver and other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs, and how these molecules alter metabolism in liver, muscle, adipose tissue, and pancreas to induce insulin resistance. We also synthesize the limited information that indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for intertissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD.

Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting Cd36 in the prostate of cancer-susceptible Pten−/− mice reduced fatty acid uptake and the abundance of oncogenic signaling lipids and slowed cancer progression. Moreover, CD36 antibody therapy reduced cancer severity in patient-derived xenografts. We further demonstrated cross-talk between fatty acid uptake and de novo lipogenesis and found that dual targeting of these pathways more potently inhibited proliferation of human cancer-derived organoids compared to the single treatments. These findings identify a critical role for CD36-mediated fatty acid uptake in prostate cancer and suggest that targeting fatty acid uptake might be an effective strategy for treating prostate cancer.

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This article is available online at http://www.jlr.org arisen to a great extent from excess nutrient intake, especially in the form of fat. Intake of diets rich in long-chain fatty acids (LCFAs) (>C16 ), the most common fatty acid (FA) type in Western diets, is associated with disturbances in glucose homeostasis and insulin action ( 1, 2 ). Many mechanisms have been proposed to underpin the deleterious effects of LCFAs on metabolic health, including increased infl ammation, overactivation of stress-related pathways, and inappropriate lipid accumulation in nonadipose tissues ( 1, 3 ).Interestingly, not all dietary fats induce the same degree of metabolic dysfunction. Our group and others have shown that intake of equal-caloric diets rich in mediumchain fatty acids (MCFAs) (C8-C12) decreases adiposity ( 4-6 ), increases energy expenditure ( 7,8 ), and avoids many of the detrimental effects associated with LCFA intake. The increased energy expenditure suggests that FAs are funneled into oxidative versus storage pathways, and this has previously been suggested to be due to enhanced cellular uptake and entry of MCFAs into mitochondria (especially in the liver) for oxidation. In a recent study we showed that high-fat diets enriched with MCFAs caused a marked induction in mitochondrial oxidative capacity in muscle, over and above that induced by a LCFA high-fat diet, suggesting that enhanced myocellular oxidation of MCFAs might also be a key pathway for oxidative disposal of this class of FAs ( 8 ) Press, September 27, 2013 DOI 10.1194 Contrasting metabolic effects of medium-versus long-chain fatty acids in skeletal muscle Abbreviations: ASM, acid-soluble metabolite; CPT1, carnitine palmitoyl transferase 1; DAG, diacylglycerol; DHE, dihydroethidium; ETC, electron transport chain; FRL, free radical leak; GPx, glutathione peroxidase; GSK3 ␤ , glycogen synthase kinase 3 ␤ ; IRS1, insulin receptor substrate 1; LCFA, long-chain fatty acid; LOOH, lipid hydroperoxide; MCFA, medium-chain fatty acid; RER, respiratory exchange ratio; ROS, reactive oxygen species; SDH, succinate dehydrogenase; SOD2, superoxide dismutase 2; TAG, triacylglycerol; TBARS, thiobarbituric acid reactive substances; UCP3, uncoupling protein 3. Published, JLR Papers in