•Branched chain amino acids influence aging, sarcopenia and cardiometabolic disease.•Branched chain amino acids regulate food intake, protein synthesis and insulin release.•Therapeutic effects of ...branched chain amino acids depend upon background diet.
Branched chain amino acids (BCAA: leucine, valine, isoleucine) have key physiological roles in the regulation of protein synthesis, metabolism, food intake and aging. Many studies report apparently inconsistent conclusions about the relationships between blood levels of BCAAs or dietary manipulation of BCAAs with age-related changes in body composition, sarcopenia, obesity, insulin and glucose metabolism, and aging biology itself. These divergent results can be resolved by consideration of the role of BCAAs as signalling molecules and the bidirectional mechanistic relationship between BCAAs and some aging phenotypes. The effects of BCAAs are also influenced by the background nutritional composition such as macronutrient ratios and imbalance with other amino acids. Understanding the interaction between BCAAs and other components of the diet may provide new opportunities for influencing age-related outcomes through manipulation of dietary BCAAs together with titration of macronutrient ratios and other amino acids.
The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional ...modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.
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•Food intake is regulated primarily by dietary protein and carbohydrate•Low-protein, high-carbohydrate diets are associated with the longest lifespans•Energy reduction from high-protein diets or dietary dilution does not extend life•Diet influences hepatic mTOR via branched-chain amino acids and glucose
Solon-Biet et al. look at whether health and aging are influenced by macronutrient balance or calorie intake in mice by investigating the effects of diets differing in protein, carbohydrate, and fat content. Diets low in protein and high in carbohydrates increase lifespan, while calorie restriction through high-protein diets does not extend life.
For over half a century, researchers have been feeding different diets to rodents to examine the effects of macronutrients on whole body and tissue insulin action. During this period, the number of ...different diets and the source of macronutrients employed have grown dramatically. Because of the large heterogeneity in both the source and percentage of different macronutrients used for studies, it is not surprising that different high-calorie diets do not produce the same changes in insulin action. Despite this, diverse high-calorie diets continue to be employed in an attempt to generate a "generic" insulin resistance. The high-fat diet in particular varies greatly between studies with regard to the source, complexity, and ratio of dietary fat, carbohydrate, and protein. This review examines the range of rodent dietary models and methods for assessing insulin action. In almost all studies reviewed, rodents fed diets that had more than 45% of dietary energy as fat or simple carbohydrates had reduced whole body insulin action compared with chow. However, different high-calorie diets produced significantly different effects in liver, muscle, and whole body insulin action when insulin action was measured by the hyperinsulinemic-euglycemic clamp method. Rodent dietary models remain an important tool for exploring potential mechanisms of insulin resistance, but more attention needs to be given to the total macronutrient content and composition when interpreting dietary effects on insulin action.
Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are ...beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1α, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging.
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•Calorie restriction (CR) and low-protein, high-carb (LPHC) diets improve health•Hippocampus RNA expression is positively influenced by CR and LPHC diets•Nutrient-sensing pathways are similarly influenced by CR and LPHC diets•CR and LPHC diets positively influence dendritic spines and cognitive function
Calorie restriction (CR) and ad libitum low-protein, high-carbohydrate (LPHC) diets improve cardiometabolic health in mice. Wahl et al. show that, like healthspan, CR and LPHC diets positively affect hippocampus biology in mice by influencing hippocampus gene expression, nutrient-sensing pathways, dendritic morphology, and cognition.
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress have been implicated in hepatic steatosis and insulin resistance. The present study investigated their roles in the development of ...hepatic steatosis and insulin resistance during de novo lipogenesis (DNL) compared to extrahepatic lipid oversupply. Male C57BL/6J mice were fed either a high fructose (HFru) or high fat (HFat) diet to induce DNL or lipid oversupply in/to the liver. Both HFru and HFat feeding increased hepatic triglyceride within 3 days (by 3.5 and 2.4 fold) and the steatosis remained persistent from 1 week onwards (p<0.01 vs Con). Glucose intolerance (iAUC increased by ∼60%) and blunted insulin-stimulated hepatic Akt and GSK3β phosphorylation (∼40-60%) were found in both feeding conditions (p<0.01 vs Con, assessed after 1 week). No impairment of mitochondrial function was found (oxidation capacity, expression of PGC1α, CPT1, respiratory complexes, enzymatic activity of citrate synthase & β-HAD). As expected, DNL was increased (∼60%) in HFru-fed mice and decreased (32%) in HFat-fed mice (all p<0.05). Interestingly, associated with the upregulated lipogenic enzymes (ACC, FAS and SCD1), two (PERK/eIF2α and IRE1/XBP1) of three ER stress pathways were significantly activated in HFru-fed mice. However, no significant ER stress was observed in HFat-fed mice during the development of hepatic steatosis. Our findings indicate that HFru and HFat diets can result in hepatic steatosis and insulin resistance without obvious mitochondrial defects via different lipid metabolic pathways. The fact that ER stress is apparent only with HFru feeding suggests that ER stress is involved in DNL per se rather than resulting from hepatic steatosis or insulin resistance.
Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed ...to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.
Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver ...of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity.
Elevated branched chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when ...dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets leads to hyperphagia, obesity and reduced lifespan. These effects are not due to elevated BCAA
or hepatic mTOR activation, but rather due to a shift in the relative quantity of dietary BCAAs and other AAs, notably tryptophan and threonine. Increasing the ratio of BCAAs to these AAs resulted in hyperphagia and is associated with central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averts the health costs of a high BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes need not be due to intrinsic toxicity but, rather, a consequence of hyperphagia driven by AA imbalance.
Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve
High-Fat Diet–Induced Insulin Resistance
Clinton R. Bruce 1 2 ,
Andrew ...J. Hoy 2 ,
Nigel Turner 2 ,
Matthew J. Watt 3 4 ,
Tamara L. Allen 1 ,
Kevin Carpenter 5 6 ,
Gregory J. Cooney 2 ,
Mark A. Febbraio 1 and
Edward W. Kraegen 2
1 Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
2 Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
3 St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia
4 Department of Physiology, Monash University, Clayton, Victoria, Australia
5 Department of Biochemical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
6 Discipline of Genetic Medicine, University of Sydney, New South Wales, Australia
Corresponding author: Clinton R. Bruce, clinton.bruce{at}baker.edu.au
Abstract
OBJECTIVE— Skeletal muscle insulin resistance is associated with lipid accumulation, but whether insulin resistance is due to reduced
or enhanced flux of long-chain fatty acids into the mitochondria is both controversial and unclear. We hypothesized that skeletal
muscle–specific overexpression of the muscle isoform of carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls
the entry of long-chain fatty acyl CoA into mitochondria, would enhance rates of fatty acid oxidation and improve insulin
action in muscle in high-fat diet insulin-resistant rats.
RESEARCH DESIGN AND METHODS— Rats were fed a standard (chow) or high-fat diet for 4 weeks. After 3 weeks, in vivo electrotransfer was used to overexpress
the muscle isoform of CPT1 in the distal hindlimb muscles (tibialis anterior and extensor digitorum longus EDL). Skeletal
muscle insulin action was examined in vivo during a hyperinsulinemic-euglycemic clamp.
RESULTS— In vivo electrotransfer produced a physiologically relevant increase of ∼20% in enzyme activity; and although the high-fat
diet produced insulin resistance in the sham-treated muscle, insulin action was improved in the CPT1-overexpressing muscle.
This improvement was associated with a reduction in triacylglycerol content, the membrane-to-cytosolic ratio of diacylglycerol,
and protein kinase C θ activity. Importantly, overexpression of CPT1 did not affect markers of mitochondrial capacity or function,
nor did it alter skeletal muscle acylcarnitine profiles irrespective of diet.
CONCLUSIONS— Our data provide clear evidence that a physiological increase in the capacity of long-chain fatty acyl CoA entry into mitochondria
is sufficient to ameliorate lipid-induced insulin resistance in muscle.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 December 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.
Accepted December 2, 2008.
Received August 5, 2008.
DIABETES
In recent years, reversible lysine acylation of proteins has emerged as a major post-translational modification across the cell, and importantly has been shown to regulate many proteins in ...mitochondria. One key family of deacylase enzymes is the sirtuins, of which SIRT3, SIRT4, and SIRT5 are localised to the mitochondria and regulate acyl modifications in this organelle.
In this review we discuss the emerging role of lysine acylation in the mitochondrion and summarise the evidence that proposes mitochondrial sirtuins are important players in the modulation of mitochondrial energy metabolism in response to external nutrient cues, via their action as lysine deacylases. We also highlight some key areas of mitochondrial sirtuin biology where future research efforts are required.
Lysine deacetylation appears to play some role in regulating mitochondrial metabolism. Recent discoveries of new enzymatic capabilities of mitochondrial sirtuins, including desuccinylation and demalonylation activities, as well as an increasing list of novel protein substrates have identified many new questions regarding the role of mitochondrial sirtuins in the regulation of energy metabolism.
Dynamic changes in the regulation of mitochondrial metabolism may have far-reaching consequences for many diseases, and despite promising initial findings in knockout animals and cell models, the role of the mitochondrial sirtuins requires further exploration in this context. This article is part of a Special Issue entitled Frontiers of mitochondrial research.
•The scope and role of lysine acylation in mitochondria is reviewed.•Sirtuin enzymes are located in mitochondria and regulate metabolic enzymes.•SIRT3 deacetylates many proteins, but its role in metabolism requires more study.•SIRT4 and SIRT5 have few validated targets and are an exciting area of new research.
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