Sex and genetic background define the metabolic, physiologic, and molecular response to protein restriction.

Low-protein diets promote metabolic health in humans and rodents. Despite evidence that sex and genetic background are key factors in the response to diet, most protein intake studies examine only a single strain and sex of mice. Using multiple strains and both sexes of mice, we find that improvements in metabolic health in response to reduced dietary protein strongly depend on sex and strain. While some phenotypes were conserved across strains and sexes, including increased glucose tolerance and energy expenditure, we observed high variability in adiposity, insulin sensitivity, and circulating hormones. Using a multi-omics approach, we identified mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype, providing molecular insight into the differential response to protein restriction. Our results highlight the importance of sex and genetic background in the response to dietary protein level, and the potential importance of a personalized medicine approach to dietary interventions.

Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice.

Calorie restriction (CR) promotes healthy ageing in diverse species. Recently, it has been shown that fasting for a portion of each day has metabolic benefits and promotes lifespan. These findings complicate the interpretation of rodent CR studies, in which animals typically eat only once per day and rapidly consume their food, which collaterally imposes fasting. Here we show that a prolonged fast is necessary for key metabolic, molecular and geroprotective effects of a CR diet. Using a series of feeding regimens, we dissect the effects of calories and fasting, and proceed to demonstrate that fasting alone recapitulates many of the physiological and molecular effects of CR. Our results shed new light on how both when and how much we eat regulate metabolic health and longevity, and demonstrate that daily prolonged fasting, and not solely reduced caloric intake, is likely responsible for the metabolic and geroprotective benefits of a CR diet.

Inositol-Requiring Enzyme 1α-Mediated Synthesis of Monounsaturated Fatty Acids as a Driver of B Cell Differentiation and Lupus-like Autoimmune Disease.

OBJECTIVE: To explore the molecular mechanisms underlying dysregulation of lipid metabolism in the pathogenesis of systemic lupus erythematosus (SLE). METHODS: B cells in peripheral blood from patients with SLE and healthy controls were stained with BODIPY dye for detection of lipids. Mice with targeted knockout of genes for B cell-specific inositol-requiring enzyme 1α (IRE-1α) and stearoyl-coenzyme A desaturase 1 (SCD-1) were used for studying the influence of the IRE-1α/SCD-1/SCD-2 pathway on B cell differentiation and autoantibody production. The preclinical efficacy of IRE-1α suppression as a treatment for lupus was tested in MRL.Faslpr mice. RESULTS: In cultures with mouse IRE-1α-null B cells, supplementation with monounsaturated fatty acids largely rescued differentiation of plasma cells from B cells, indicating that the compromised capacity of B cell differentiation in the absence of IRE-1α may be attributable to a defect in monounsaturated fatty acid synthesis. Moreover, activation with IRE-1α/X-box binding protein 1 (XBP-1) was required to facilitate B cell expression of SCD-1 and SCD-2, which are 2 critical enzymes that catalyze monounsaturated fatty acid synthesis. Mice with targeted Scd1 gene deletion displayed a phenotype that was similar to that of IRE-1α-deficient mice, with diminished B cell differentiation into plasma cells. Importantly, in B cells from patients with lupus, both IRE-1α expression and Xbp1 messenger RNA splicing were significantly increased, and this was positively correlated with the expression of both Scd1 and Scd2 as well as with the amount of B cell lipid deposition. In MRL.Faslpr mice, both genetic and pharmacologic suppression of IRE-1α protected against the pathologic development and progression of lupus-like autoimmune disease. CONCLUSION: The results of this study reveal a molecular link in the dysregulation of lipid metabolism in the pathogenesis of lupus, demonstrating that the IRE-1α/XBP-1 pathway controls plasma cell differentiation through SCD-1/SCD-2-mediated monounsaturated fatty acid synthesis. These findings provide a rationale for targeting IRE-1α and monounsaturated fatty acid synthesis in the treatment of patients with SLE.

Next Generation Strategies for Geroprotection via mTORC1 Inhibition.

Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) with the pharmaceutical rapamycin prolongs the lifespan and healthspan of model organisms including rodents, with evidence now emerging that rapamycin and its analogs may also have rejuvenative effects in dogs and humans. However, the side effects associated with long-term rapamycin treatment, many of which are due to inhibition of a second mTOR complex, mTORC2, have seemed to preclude the routine use of rapamycin as a therapy for age-related diseases. Here, we discuss recent findings suggesting that strong, chronic inhibition of both mTOR complexes may not be necessary to realize the geroprotective effects of rapamycin. Instead, modestly but specifically inhibiting mTORC1 via a variety of emerging techniques, including intermittent or transient treatment with rapamycin derivatives, or specific dietary regimens, may be sufficient to promote health and longevity with reduced side effects. We will also discuss prospects for the development of new molecules that, by harnessing the detailed molecular understanding of mTORC1 signaling developed over the last decade, will provide new routes to the selective inhibition of mTORC1. We conclude that therapies based on the selective inhibition of mTORC1 may soon permit the safer treatment of diseases of aging.

Interleukin-6 derived from cutaneous deficiency of stearoyl-CoA desaturase- 1 may mediate metabolic organ crosstalk among skin, adipose tissue and liver.

Stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme that adds a double bond at the delta 9 position of stearate (C18: 0) and palmitate (C16: 0), has been proven to be important in the development of obesity. Mice with skin-specific deficiency of SCD1 (SKO) display increased whole-body energy expenditure, which is protective against adiposity from a high-fat diet because it improves glucose clearance, insulin sensitivity, and hepatic steatosis. Of note, these mice also display elevated levels of the "pro-inflammatory" plasma interleukin-6 (IL-6). In whole skin of SKO mice, IL-6 mRNA levels are increased, and protein expression is evident in hair follicle cells and in keratinocytes. Recently, the well-known role of IL-6 in causing white adipose tissue lipolysis has been linked to indirectly activating the gluconeogenic enzyme pyruvate carboxylase 1 in the liver, thereby increasing hepatic glucose production. In this study, we suggest that skin-derived IL-6 leads to white adipose tissue lipolysis, which contributes to the lean phenotype of SKO mice without the incidence of meta-inflammation that is associated with IL-6 signaling.

A Discussion on the Relationship between Skin Lipid Metabolism and Whole-Body Glucose and Lipid Metabolism: Systematic Review.

The obesity epidemic is a costly public health crisis that is not improving. In addition to the stigma and discomfort associated with carrying extra weight (at the expense of range of movement), obesity also goes hand-in-hand with co-morbidities like fatty liver disease, diabetes, cardiovascular disease, and increased risk of some forms of cancer. Currently there are no long-lasting treatments for obesity other than diet and exercise, which are not feasible for many populations that may not be equipped with the resources and/or support needed to lead a healthy lifestyle. Although there have been some pharmacological breakthroughs for treating obesity, each FDA-approved drug comes with unpleasant side-effects that make adherence unlikely. As a result, alternate approaches are necessary. In this review, we outline the relationship between skin lipid metabolism and whole-body glucose and lipid metabolism. Specifically, by summarizing studies that employed mice that were genetically modified to interrupt lipid metabolism in the skin. As a result, we propose that skin might be an overlooked, but viable target for combating obesity.

Increased hydrophilic plasma bile acids are correlated with protection from adiposity in skin-specific stearoyl-CoA desaturase-1 deficient mice.

Stearoyl-CoA desaturase 1 (SCD1) catalyzes the rate limiting step in monounsaturated fatty acid synthesis by inserting a double bond at the delta-9 position of long-chain fatty acids. SCD1 converts stearate (18:0) to oleate (18:1n9) and palmitate (16:0) to palmitoleate (16:1n7), respectively. Mice with global and skin-specific deletion (SKO) of SCD1 exhibit increased whole body energy expenditure and protection against diet-induced adiposity, hepatic steatosis, insulin sensitivity and glucose intolerance. The mechanisms that link cutaneous lipid homeostasis with whole body energy balance are presently unknown. In this study, we reveal that SKO mice demonstrate increased skin surface free cholesterol, decreased circulating total cholesterol and increased taurine-conjugated and hydrophilic bile acids. Tauro-ß-muricholic acid, which is a marker of extrahepatic bile acid synthesis, is significantly elevated in SKO plasma. Bile acid signaling through the bile acid-specific receptor TGR5 is known to be protective against obesity and metabolic disease; a phenotype that is similar to SKO mice. We therefore examined TGR5 expression and its downstream mediator, DIO2, in various tissues and found that both TGR5 and DIO2 expression were significantly increased in brown adipose tissue. In sum, we suggest that skin-derived bile acids are involved in the lean and metabolically healthy phenotype of SKO mice.