Protein restricted, high carbohydrate diets improve metabolic health in rodents, yet the precise dietary components that are responsible for these effects have not been identified. Further, the applicability of these studies to humans is unclear. Here, we demonstrate in a randomized controlled trial that a moderately protein restricted (PR) diet also improves markers of metabolic health in humans. Intriguingly, we find that feeding mice a diet specifically reduced in branched chain amino acids (BCAAs) is sufficient to improve glucose tolerance and body composition equivalently to a PR diet, via metabolically distinct pathways. Our results highlight a critical role for dietary quality at the level of amino acids in the maintenance of metabolic health, and suggest that diets specifically reduced in BCAAs, or pharmacological interventions in this pathway, may offer a translatable way to achieve many of the metabolic benefits of a PR diet.

Key pointsr We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, modestly improves glucose tolerance and slows fat mass gain.r In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice.r Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high-fat, high-sugar diet.r A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure.r We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets.Abstract Obesity and diabetes are increasing problems around the world, and although even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Branched-chain amino acids (BCAAs; leucine, isoleucine and valine) are elevated in the blood of obese, insulin-resistant humans and rodents. We recently demonstrated that specifically reducing dietary levels of BCAAs has beneficial effects on the metabolic health of young, growing mice, improving glucose tolerance and modestly slowing fat mass gain. In the present study, we examine the hypothesis that reducing dietary BCAAs will promote weight loss, reduce adiposity, and improve blood glucose control in diet-induced obese mice with pre-existing metabolic syndrome. We find that specifically reducing dietary BCAAs rapidly reverses diet-induced obesity and improves glucoregulatory control in diet-induced obese mice. Most dramatically, mice eating an otherwise unhealthy high-calorie, high-sugar Western diet with reduced levels of BCAAs lost weight and fat mass rapidly until regaining a normal weight. Importantly, this normalization of weight was mediated not by caloric restriction or increased activity, but by increased energy expenditure, and was accompanied by a transient induction of the energy balance regulating hormone FGF21 (fibroblast growth factor 21). Consumption of a Western diet reduced in BCAAs was also accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Our results link dietary BCAAs with the regulation of metabolic health and energy balance in obese animals, and suggest that specifically reducing dietary BCAAs may represent a highly translatable option for the treatment of obesity and insulin resistance.

Yu and Richardson et al. find that restriction of dietary isoleucine or valine promotes metabolic health in mice and that restriction of dietary isoleucine is required for the metabolic benefits of a low-protein diet. Furthermore, higher dietary isoleucine levels are associated with increased BMI in humans.

NIH (DK107646, DK112282, P20GM103527, and by CTSA grant UL1TR001998).

Homeostatic temperature regulation is fundamental to mammalian physiology and is controlled by acute and chronic responses of local, endocrine and nervous regulators. Here, we report that loss of the heparan sulfate proteoglycan, syndecan-1, causes a profoundly depleted intradermal fat layer, which provides crucial thermogenic insulation for mammals. Mice without syndecan-1 enter torpor upon fasting and show multiple indicators of cold stress, including activation of the stress checkpoint p38α in brown adipose tissue, liver and lung. The metabolic phenotype in mutant mice, including reduced liver glycogen, is rescued by housing at thermoneutrality, suggesting that reduced insulation in cool temperatures underlies the observed phenotypes. We find that syndecan-1, which functions as a facultative lipoprotein uptake receptor, is required for adipocyte differentiation in vitro. Intradermal fat shows highly dynamic differentiation, continuously expanding and involuting in response to hair cycle and ambient temperature. This physiology probably confers a unique role for Sdc1 in this adipocyte sub-type. The PPARγ agonist rosiglitazone rescues Sdc1−/− intradermal adipose tissue, placing PPARγ downstream of Sdc1 in triggering adipocyte differentiation. Our study indicates that disruption of intradermal adipose tissue development results in cold stress and complex metabolic pathology.

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Scott syndrome (SS) is a bleeding disorder characterized by a failure to expose phosphatidylserine (PS) to the outer leaflet of the platelet plasma membrane. Because the adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) is implicated in the exofacial translocation of PS, we assessed its role in the pathophysiology of a patient with SS. Substantially reduced levels of ABCA1 mRNA were found in the patient's leukocytes, compared with controls. The SS patient was heterozygous for a novel missense mutation c.6064G>A (ABCA1 R1925Q), absent from unaffected family members and controls. Both mutant and wild-type alleles were reduced in mRNA expression, and no causative mutation for this phenomenon was identified in the ABCA1 gene or its proximal promoter, suggesting a putative second mutation in a trans-acting regulatory gene may also be involved in the disorder in this patient. In vitro expression studies showed impaired trafficking of ABCA1 R1925Q to the plasma membrane. Overexpression of wild-type ABCA1 in SS lymphocytes complemented the Ca 2؉ -dependent PS exposure at the cell surface. These data identify a mutation in ABCA1 that contributes to the defective PS translocation phenotype in our patient with SS. IntroductionScott syndrome (SS) is a rare, moderately severe bleeding disorder (Online Mendelian Inheritance in Man [OMIM] database: 262890). Because only 3 patients (one American, one French, and one British) have been identified, the inheritance pattern is unknown, 1,2 and the rarity of affected individuals precludes the use of conventional mapping approaches to identify the underlying genetic lesions. Hemostatic parameters of close relatives of patients with SS exhibit significant though clinically silent defects, indicating that any defective gene has substantial penetrance in the heterozygous state, 1,2 and do not preclude the possibility that the SS phenotype reflects the interaction of 2 (or more) defective genes.The defining characteristic of SS is the absence of Ca 2ϩ -stimulated exposure of phosphatidylserine (PS) from the inner leaflet of the plasma membrane bilayer to the cell surface, which in platelets normally provides an appropriate surface for the assembly of the tenase and prothrombinase complexes of the coagulation network. This defect is also observed in Epstein-Barr virus (EBV)-transformed lymphocytes of patients with SS. The mechanism by which PS is translocated to the cell surface following Ca 2ϩ stimulation is controversial, and several proteins have been suggested as playing a role. However, both phospholipid scramblase 1 3-5 and P-glycoprotein 4,6 appear to be normal in patients with SS.The adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) has been implicated in PS translocation both by genetic disruption in mice 7 and chemical inhibition. 8 It is not yet clear whether ABCA1 translocates PS directly or acts as a regulator of another protein. 9 Mutations in ABCA1 underlie Tangier disease (TD) and familial high-density lipoprotein (HDL) deficiency, [1...

We have developed a rapid, simple and reliable, antibody-based flow cytometry assay for the quantitative determination of membrane proteins in human erythrocytes. Our method reveals significant differences between the expression levels of the wild-type ABCG2 protein and the heterozygous Q141K polymorphic variant. Moreover, we find that nonsense mutations on one allele result in a 50% reduction in the erythrocyte expression of this protein. Since ABCG2 polymorphisms are known to modify essential pharmacokinetic parameters, uric acid metabolism and cancer drug resistance, a direct determination of the erythrocyte membrane ABCG2 protein expression may provide valuable information for assessing these conditions or for devising drug treatments. Our findings suggest that erythrocyte membrane protein levels may reflect genotype-dependent tissue expression patterns. Extension of this methodology to other disease-related or pharmacologically important membrane proteins may yield new protein biomarkers for personalized diagnostics.