Whole milk dairy foods and cardiometabolic health: dairy fat and beyond.

Bovine dairy milk is a nutrient-rich matrix, but consumption of full-fat dairy food varieties has been claimed historically to be associated with poorer cardiometabolic health, a notion often attributed to the saturated fat content. However, continued investigation that includes observational studies and randomized controlled trials (RCTs) provide evidence that favorably supports full-fat dairy foods and their bioactive components on cardiometabolic health. This review addresses this controversy by examining the evidence surrounding full-fat dairy foods and their implications for human health. Dairy foods are heterogeneous, not just in their fat content but also in other compositional aspects within and between fermented (e.g., yogurt, cheese) and nonfermented products (e.g., milk) that could differentially influence cardiometabolic health. Drawing from complementary lines of evidence from epidemiological studies and RCTs, this review describes the health effects of dairy foods regarding their fat content, as well as their polar lipids that are concentrated in the milk fat globule fraction. Observational studies have limitedly supported the consumption of full-fat dairy to protect against cardiometabolic disorders. However, this framework has been disputed by RCTs indicating that dairy foods, regardless of their fat content or fermentation, are not detrimental to cardiometabolic health and may instead alleviate certain cardiometabolic risk factors. As dietary recommendations evolve, which currently indicate to avoid full-fat dairy foods, it is essential to consider the totality of evidence, especially from RCTs, while also recognizing that investigation is needed to evaluate the complexity of dairy foods within diverse dietary patterns and their impacts on cardiometabolic health.

Whole-Milk Dairy Foods: Biological Mechanisms Underlying Beneficial Effects on Risk Markers for Cardiometabolic Health.

Lifestyle modifications that include adherence to healthy dietary patterns that are low in saturated fat have been associated with reduced risk for cardiovascular disease, the leading cause of death globally. Whole-milk dairy foods, including milk, cheese, and yogurt, are leading sources of saturated fat in the diet. Dietary guidelines around the world recommend the consumption of low-fat and fat-free dairy foods to obtain overall healthy dietary patterns that help meet nutrient recommendations while keeping within recommended calorie and saturated fat limitations. A body of observational and clinical evidence indicates, however, that whole-milk dairy food consumption, despite saturated fat content, does not increase the risk for cardiovascular disease. This review describes the proposed biological mechanisms underlying inverse associations between whole-milk dairy food consumption and risk markers for cardiometabolic health, such as altered lipid digestion, absorption, and metabolism; influence on the gut microflora; and regulation of oxidative stress and inflammatory responses. The dairy food matrix, a term used to describe how the macronutrients and micronutrients and other bioactive components of dairy foods are differentially packaged and compartmentalized among fluid milk, cheese, and yogurt, may dictate how each affects cardiovascular risk. Current evidence indicates consideration of dairy foods as complex food matrices, rather than delivery systems for isolated nutrients, such as saturated fatty acids, is warranted.

The Relationship between Whole-Milk Dairy Foods and Metabolic Health Highlights an Opportunity for Dietary Fat Recommendations to Evolve with the State of the Science.

The science of dietary fats has evolved, and a body of evidence indicates they are complex bioactive nutrients that have different effects on health depending on their food source, chain length, degree of saturation, and other factors that can be affected by food processing, handling, and storage. As such, it is becoming increasingly clear that the effects of foods on obesity and metabolic health cannot be predicted simply with their fat content. The aim of this opinion article is to provide a brief overview of select recent research on the effects of whole-milk dairy foods on body composition and indicators of metabolic health across the lifespan to show the gap between current knowledge and dietary guidance. As the state of the science on dietary fats and human health evolves to consider the complexity of food matrices, the total nutrient package they deliver, and the health impacts associated with dietary patterns, so too must guidelines for dietary fat.

Harnessing the Magic of the Dairy Matrix for Next-Level Health Solutions: A Summary of a Symposium Presented at Nutrition 2022.

An emerging body of scientific evidence demonstrates that the food matrix-the interaction among nutrients, bioactive components, and physical structure of a food-can affect health in significant, unexpected ways beyond its individual nutrients. In particular, research suggests that consumption of dairy foods such as milk, yogurt, and cheese may affect human health in a matrix-dependent fashion. To disseminate and discuss the growing body of evidence surrounding the role of the dairy food matrix on cardiometabolic health, 3 expert researchers on the topic of the food matrix shared the latest science in a session entitled "Next-Level Health Solutions: The Magic of the Matrix" at the American Society for Nutrition's 2022 LIVE ONLINE Conference. This article is a summary of the literature presented and discussed during that session. A substantial body of literature demonstrates that full-fat dairy foods, particularly fermented dairy foods, may beneficially modulate cardiometabolic outcomes depending on an individual's health status. These findings have important implications for current authoritative dietary guidance that recommends the consumption of low-fat or fat-free dairy foods. Furthermore, this evidence may inform practical applications of harnessing dairy's unique profile of bioactives for health promotion and disease prevention at the individual and community levels.

Perspective: Seeing the Forest Through the Trees: The Importance of Food Matrix in Diet Quality and Human Health.

Poor nutrition is linked to morbidity and mortality globally. The nutrition transition toward diets composed of high amounts of ultraprocessed foods that are more refined, calorie-dense, and poor in nutrients is considered a factor in the rise of diet-related metabolic diseases in low- and middle-income countries. Historically, nutrition strategies aimed at mitigating metabolic diseases linked to suboptimal diets have targeted isolated nutrients such as fats; however, they overlook the complexity and importance of whole foods and food matrices, which can lead to unintended consequences such as avoidance of nutrient-dense foods. Dairy foods, such as milk, cheese, and yogurt, are underconsumed nutrient-dense foods that often fall in the cross-hairs of reductionist nutrition strategies because of their contribution of calories, saturated fat, and sodium to the diet. This article highlights dairy foods as an example for exploring the complex matrices of food, nutrients, and other bioactive components that are associated with improved nutrient status and reduced risk of metabolic diseases while considering a holistic approach to improving diet quality and human health.

The Influence of Viral Infections on Iron Homeostasis and the Potential for Lactoferrin as a Therapeutic in the Age of the SARS-CoV-2 Pandemic.

The association of hyperinflammation and hyperferritinemia with adverse outcomes in SARS-CoV-2-infected patients suggests an integral role for iron homeostasis in pathogenesis, a commonly described symptom of respiratory viral infections. This dysregulated iron homeostasis results in viral-induced lung injury, often lasting long after the acute viral infection; however, much remains to be understood mechanistically. Lactoferrin is a multipurpose glycoprotein with key immunomodulatory, antimicrobial, and antiviral functions, which can be found in various secreted fluids, but is most abundantly characterized in milk from all mammalian species. Lactoferrin is found at its highest concentrations in primate colostrum; however, the abundant availability of bovine-dairy-derived lactoferrin (bLf) has led to the use of bLf as a functional food. The recent research has demonstrated the potential value of bovine lactoferrin as a therapeutic adjuvant against SARS-CoV-2, and herein this research is reviewed and the potential mechanisms of therapeutic targeting are considered.

Cardiometabolic health benefits of dairy-milk polar lipids.

Low-quality dietary patterns impair cardiometabolic health by increasing the risk of obesity-related disorders. Cardiometabolic risk relative to dairy-food consumption continues to be a controversial topic, due to recommendations that endorse low-fat and nonfat dairy foods over full-fat varieties despite accumulated evidence that does not strongly support these recommendations. Controlled human studies and mechanistic preclinical investigations support that full-fat dairy foods decrease cardiometabolic risk by promoting gut health, reducing inflammation, and managing dyslipidemia. These gut- and systemic-level cardiometabolic benefits are attributed, at least in part, to milk polar lipids (MPLs) derived from the phospholipid- and sphingolipid-rich milk fat globule membrane that is of higher abundance in full-fat dairy milk. The controversy surrounding full-fat dairy food consumption is discussed in this review relative to cardiometabolic health and MPL bioactivities that alleviate dyslipidemia, shift gut microbiota composition, and reduce inflammation. This summary, therefore, is expected to advance the understanding of full-fat dairy foods through their MPLs and the need for translational research to establish evidence-based dietary recommendations.

Association of Milk Consumption and Vitamin D Status in the US Population by Ethnicity: NHANES 2001-2010 Analysis.

Vitamin D has been identified as a nutrient of public health concern, and higher intake of natural or fortified food sources of vitamin D, such as milk, are encouraged by the 2015-2020 Dietary Guidelines for Americans. We, therefore, examined the association of milk consumption and vitamin D status in the United States (US) population. Twenty-four-hour dietary recall data and serum 25(OH)D concentrations were obtained from the National Health and Nutrition Examination Survey 2001-2010 and were analyzed by linear and logistic regression after adjusting for anthropometric and demographic variables. Significance was set at p < 0.05. Approximately 57-80% children and 42-60% adults were milk consumers. Milk intake (especially reduced-fat, low fat and no-fat milk) was positively associated (plinear trend < 0.05) with serum vitamin D status and with a 31-42% higher probability of meeting recommended serum vitamin D (>50 nmol/L) levels among all age groups. Serum vitamin D status was also associated with both type and amount of milk intake depending upon the age and ethnicity. In conclusion, the results indicate that milk consumers consistently have higher serum vitamin D levels and higher probability of meeting recommended levels. Therefore, increasing milk intake may be an effective strategy to improve the vitamin D status of the US population.

Branched-Chain Fatty Acids-An Underexplored Class of Dairy-Derived Fatty Acids.

Dairy fat and its fatty acids (FAs) have been shown to possess pro-health properties that can support health maintenance and disease prevention. In particular, branched-chain FAs (BCFAs), comprising approximately 2% of dairy fat, have recently been proposed as bioactive molecules contributing to the positive health effects associated with the consumption of full-fat dairy products. This narrative review evaluates human trials assessing the relationship between BCFAs and metabolic risk factors, while potential underlying biological mechanisms of BCFAs are explored through discussion of studies in animals and cell lines. In addition, this review details the biosynthetic pathway of BCFAs as well as the content and composition of BCFAs in common retail dairy products. Research performed with in vitro models demonstrates the potent, structure-specific properties of BCFAs to protect against inflammation, cancers, and metabolic disorders. Yet, human trials assessing the effect of BCFAs on disease risk are surprisingly scarce, and to our knowledge, no research has investigated the specific role of dietary BCFAs. Thus, our review highlights the critical need for scientific inquiry regarding dairy-derived BCFAs, and the influence of this overlooked FA class on human health.

Milk Polar Lipids: Underappreciated Lipids with Emerging Health Benefits.

Milk fat is encased in a polar lipid-containing tri-layer milk fat globule membrane (MFGM), composed of phospholipids (PLs) and sphingolipids (SLs). Milk PLs and SLs comprise about 1% of total milk lipids. The surfactant properties of PLs are important for dairy products; however, dairy products vary considerably in their polar lipid to total lipid content due to the existence of dairy foods with different fat content. Recent basic science and clinical research examining food sources and health effects of milk polar lipids suggest they may beneficially influence dysfunctional lipid metabolism, gut dysbiosis, inflammation, cardiovascular disease, gut health, and neurodevelopment. However, more research is warranted in clinical studies to confirm these effects in humans. Overall, there are a number of potential effects of consuming milk polar lipids, and they should be considered as food matrix factors that may directly confer health benefits and/or impact effects of other dietary lipids, with implications for full-fat vs. reduced-fat dairy.

Establishing the Link Between Lean Mass and Grip Strength Cut Points With Mobility Disability and Other Health Outcomes: Proceedings of the Sarcopenia Definition and Outcomes Consortium Conference.

BACKGROUND: Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut points for lean mass and/or muscle strength that identify people at increased risk of mobility disability. We describe here the proceedings of a meeting of SDOC and other experts to discuss strategic considerations in the development of evidence-based sarcopenia definition. METHODS: Presentations and panel discussions reviewed the usefulness of sarcopenia as a biomarker, the analytical approach used by SDOC to establish cut points, and preliminary findings, and provided strategic direction to develop an evidence-based definition of sarcopenia. RESULTS: The SDOC assembled data from eight epidemiological cohorts consisting of 18,831 participants, clinical populations from 10 randomized trials and observational studies, and 2 nationally representative cohorts. In preliminary assessments, grip strength or grip strength divided by body mass index was identified as discriminators of risk for mobility disability (walking speed <0.8 m/s), whereas dual-energy X-ray absorptiometry-derived lean mass measures were not good discriminators of mobility disability. Candidate definitions based on grip strength variables were associated with increased risk of mortality, falls, mobility disability, and instrumental activities of daily living disability. The prevalence of low grip strength increased with age. The attendees recommended the establishment of an International Expert Panel to review a series of position statements on sarcopenia definition that are informed by the findings of the SDOC analyses and synthesis of literature. CONCLUSIONS: International consensus on an evidence-based definition of sarcopenia is needed. Grip strength-absolute or adjusted for body mass index-is an important discriminator of mobility disability and other endpoints. Additional research is needed to develop a predictive risk model that takes into account sarcopenia components as well as age, sex, race, and comorbidities.

Dairy Fat Consumption and the Risk of Metabolic Syndrome: An Examination of the Saturated Fatty Acids in Dairy.

Lifestyle is a key modifiable risk factor involved in the manifestation of metabolic syndrome and, in particular, diet plays a pivotal role in its prevention and development. Current dietary guidelines discourage the consumption of saturated fat and dietary sources rich in saturated fat, such as dairy products, despite data suggesting that full-fat dairy consumption is protective against metabolic syndrome. This narrative review assessed the recent epidemiological and clinical research that examined the consumption of dairy-derived saturated fatty acids (SFA) on metabolic syndrome risk. In addition, this review evaluated studies of individual SFA to gain insight into the potential mechanisms at play with intake of a diet enriched with these dairy-derived fatty acids. This work underscores that SFA are a heterogenous class of fatty acids that can differ considerably in their biological activity within the body depending on their length and specific chemical structure. In summary, previous work on the impact of dairy-derived SFA consumption on disease risk suggests that there is currently insufficient evidence to support current dietary guidelines which consolidate all dietary SFA into a single group of nutrients whose consumption should be reduced, regardless of dietary source, food matrix, and composition.

Regular-Fat Dairy and Human Health: A Synopsis of Symposia Presented in Europe and North America (2014-2015).

In recent history, some dietary recommendations have treated dairy fat as an unnecessary source of calories and saturated fat in the human diet. These assumptions, however, have recently been brought into question by current research on regular fat dairy products and human health. In an effort to disseminate, explore and discuss the state of the science on the relationship between regular fat dairy products and health, symposia were programmed by dairy industry organizations in Europe and North America at The Eurofed Lipids Congress (2014) in France, The Dairy Nutrition Annual Symposium (2014) in Canada, The American Society for Nutrition Annual Meeting held in conjunction with Experimental Biology (2015) in the United States, and The Federation of European Nutrition Societies (2015) in Germany. This synopsis of these symposia describes the complexity of dairy fat and the effects regular-fat dairy foods have on human health. The emerging scientific evidence indicates that the consumption of regular fat dairy foods is not associated with an increased risk of cardiovascular disease and inversely associated with weight gain and the risk of obesity. Dairy foods, including regular-fat milk, cheese and yogurt, can be important components of an overall healthy dietary pattern. Systematic examination of the effects of dietary patterns that include regular-fat milk, cheese and yogurt on human health is warranted.

Mitochondrial 8-oxoguanine glycosylase decreases mitochondrial fragmentation and improves mitochondrial function in H9C2 cells under oxidative stress conditions.

The mitochondrial DNA base modification 8-hydroxy 2'-deoxyguanine (8-OHdG) is one of the most common DNA lesions induced by reactive oxygen species (ROS) and is considered an index of DNA damage. High levels of mitochondrial 8-OHdG have been correlated with increased mutation, deletion, and loss of mitochondrial (mt) DNA, as well as apoptosis. 8-Oxoguanosine DNA glycosylase-1 (OGG1) recognizes and removes 8-OHdG to prevent further DNA damage. We evaluated the effects of OGG1 on mtDNA damage, mitochondrial function, and apoptotic events induced by oxidative stress using H9C2 cardiac cells treated with menadione and transduced with either Adv-Ogg1 or Adv-Control (empty vector). The levels of mtDNA 8-OHdG and the presence of apurinic/apyrimidinic (AP) sites were decreased by 30% and 35%, respectively, in Adv-Ogg1 transduced cells (P < 0.0001 and P < 0.005, respectively). In addition, the expression of base excision repair (BER) pathway members APE1 and DNA polymerase γ was upregulated by Adv-Ogg1 transduction. Cells overexpressing Ogg1 had increased membrane potential (P < 0.05) and decreased mitochondrial fragmentation (P < 0.005). The mtDNA content was found to be higher in cells with increased OGG1 (P < 0.005). The protein levels of fission and apoptotic factors such as DRP1, FIS1, cytoplasmic cytochrome c, activated caspase-3, and activated caspase-9 were lower in Adv-Ogg1 transduced cells. These observations suggest that Ogg1 overexpression may be an important mechanism to protect cardiac cells against oxidative stress damage.

Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes.

BACKGROUND: Obesity is a state of subclinical inflammation resulting in loss of function of insulin receptors and decreased insulin sensitivity. Inhibition of the inflammatory enzymes, matrix metalloproteinases (MMPs), for 6 months in rodent models restores insulin receptor function and insulin sensitivity. METHODS: This 12-week double-blind, randomized, placebo (PL)-controlled proof-of-concept study was performed to determine if the MMP inhibitor (MMPI), doxycycline, decreased global markers of inflammation and enhanced muscle insulin sensitivity in obese people with type 2 diabetes (DM2). The study included non-DM2 controls (n = 15), and DM2 subjects randomized to PL (n = 13) or doxycycline 100 mg twice daily (MMPI; n = 11). All participants were evaluated on Day 1; MMPI and PL groups were also evaluated after 84 days of treatment. RESULTS: There was a significant decrease in inflammatory markers C-reactive protein (P < 0.05) and myeloperoxidase (P = 0.01) in the MMPI but not PL group. The MMPI also significantly increased skeletal muscle activated/total insulin signaling mediators: 3'phosphoinositide kinase-1 (PDK1) (p < 0.03), protein kinase B (PKB/Akt) (p < 0.004), and glycogen synthase kinase 3ß (GSK3ß) (p < 0.03). CONCLUSIONS: This study demonstrated short term treatment of people with diabetes with an MMPI resulted in decreased inflammation and improved insulin sensitivity. Larger, longer studies are warranted to determine if doxycycline can improve glucose control in people with diabetes. TRIAL REGISTRATION: Clinicaltrials.gov NCT01375491.

Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy.

We examined the role that enzymatic protein O-GlcNAcylation plays in the development of diabetic cardiomyopathy in a mouse model of Type 2 diabetes mellitus (DM2). Mice injected with low-dose streptozotocin and fed a high-fat diet developed mild hyperglycemia and obesity consistent with DM2. Studies were performed from 1 to 6 mo after initiating the DM2 protocol. After 1 mo, DM2 mice showed increased body weight, impaired fasting blood glucose, and hyperinsulinemia. Echocardiographic evaluation revealed left ventricular diastolic dysfunction by 2 mo and O-GlcNAcylation of several cardiac proteins and of nuclear transcription factor Sp1. By 4 mo, systolic dysfunction was observed and sarcoplasmic reticulum Ca(2+) ATPase expression decreased by 50%. Fibrosis was not observed at any timepoint in DM2 mice. Levels of the rate-limiting enzyme of the hexosamine biosynthetic pathway, glutamine:fructose-6-phosphate amidotransferase (GFAT) were increased as early as 2 mo. Fatty acids, which are elevated in DM2 mice, can possibly be linked to excessive protein O-GlcNAcylation levels, as cultured cardiac myocytes in normal glucose treated with oleic acid showed increased O-GlcNAcylation and GFAT levels. These data indicate that the early onset of diastolic dysfunction followed by the loss of systolic function, in the absence of cardiac hypertrophy or fibrosis, is associated with increased cardiac protein O-GlcNAcylation and increased O-GlcNAcylation levels of key calcium-handling proteins. A link between excessive protein O-GlcNAcylation and cardiac dysfunction is further supported by results showing that reducing O-GlcNAcylation by O-GlcNAcase overexpression improved cardiac function in the diabetic mouse. In addition, fatty acids play a role in stimulating excess O-GlcNAcylation. The nature and time course of changes observed in cardiac function suggest that protein O-GlcNAcylation plays a mechanistic role in the triggering of diabetic cardiomyopathy in DM2.

Menhaden oil decreases high-fat diet-induced markers of hepatic damage, steatosis, inflammation, and fibrosis in obese Ldlr-/- mice.

The frequency of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with obesity in the United States. NASH is progressive and characterized by hepatic damage, inflammation, fibrosis, and oxidative stress. Because C20-22 (n-3) PUFA are established regulators of lipid metabolism and inflammation, we tested the hypothesis that C20-22 (n-3) PUFA in menhaden oil (MO) prevent high-fat (HF) diet-induced fatty liver disease in mice. Wild-type (WT) and Ldlr(-/-) C57BL/6J mice were fed the following diets for 12 wk: nonpurified (NP), HF with lard (60% of energy from fat), HF-high-cholesterol with olive oil (HFHC-OO; 54.4% of energy from fat, 0.5% cholesterol), or HFHC-OO supplemented with MO (HFHC-MO). When compared with the NP diet, the HF and HFHC-OO diets induced hepatosteatosis and hepatic damage [elevated plasma alanine aminotransferase (ALT) and aspartate aminotransferases] and elevated hepatic expression of markers of inflammation (monocyte chemoattractant protein-1), fibrosis (procollagen 1α1), and oxidative stress (heme oxygenase-1) (P ≤ 0.05). Hepatic damage (i.e., ALT) correlated (r = 0.74, P < 0.05) with quantitatively higher (>140%, P < 0.05) hepatic cholesterol in Ldlr(-/-) mice fed the HFHC-OO diet than WT mice fed the HF or HFHC-OO diets. Plasma and hepatic markers of liver damage, steatosis, inflammation, and fibrosis, but not oxidative stress, were lower in WT and Ldlr(-/-) mice fed the HFHC-MO diet compared with the HFHC-OO diet (P < 0.05). In conclusion, MO [C20-22 (n-3) PUFA at 2% of energy] decreases many, but not all, HF diet-induced markers of fatty liver disease in mice.

Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-ß-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes.

O-linked-N-acetyl-glucosamine glycosylation (O-GlcNAcylation) of the serine and threonine residues of cellular proteins is a dynamic process and affects phosphorylation. Prolonged O-GlcNAcylation has been linked to diabetes-related complications, including mitochondrial dysfunction. Mitochondria are dynamically remodeling organelles, that constantly fuse (fusion) and divide (fission). An imbalance of this process affects mitochondrial function. In this study, we found that dynamin-related protein 1 (DRP1) is O-GlcNAcylated in cardiomyocytes at threonine 585 and 586. O-GlcNAcylation was significantly enhanced by the chemical inhibition of N-acetyl-glucosaminidase. Increased O-GlcNAcylation decreases the phosphorylation of DRP1 at serine 637, which is known to regulate DRP1 function. In fact, increased O-GlcNAcylation augments the level of the GTP-bound active form of DRP1 and induces translocation of DRP1 from the cytoplasm to mitochondria. Mitochondrial fragmentation and decreased mitochondrial membrane potential also accompany the increased O-GlcNAcylation. In conclusion, this report shows, for the first time, that O-GlcNAcylation modulates DRP1 functionality in cardiac muscle cells.

Soraphen A, an inhibitor of acetyl CoA carboxylase activity, interferes with fatty acid elongation.

Acetyl CoA carboxylase (ACC1 and ACC2) generates malonyl CoA, a substrate for de novo lipogenesis (DNL) and an inhibitor of mitochondrial fatty acid ß-oxidation (FAO). Malonyl CoA is also a substrate for microsomal fatty acid elongation, an important pathway for saturated (SFA), mono- (MUFA) and polyunsaturated fatty acid (PUFA) synthesis. Despite the interest in ACC as a target for obesity and cancer therapy, little attention has been given to the role ACC plays in long chain fatty acid synthesis. This report examines the effect of pharmacological inhibition of ACC on DNL and palmitate (16:0) and linoleate (18:2, n-6) metabolism in HepG2 and LnCap cells. The ACC inhibitor, soraphen A, lowers cellular malonyl CoA, attenuates DNL and the formation of fatty acid elongation products derived from exogenous fatty acids, i.e., 16:0 and 18:2, n-6; IC(50)∼5nM. Elevated expression of fatty acid elongases (Elovl5, Elovl6) or desaturases (FADS1, FADS2) failed to override the soraphen A effect on SFA, MUFA or PUFA synthesis. Inhibition of fatty acid elongation leads to the accumulation of 16- and 18-carbon unsaturated fatty acids derived from 16:0 and 18:2, n-6, respectively. Pharmacological inhibition of ACC activity will not only attenuate DNL and induce FAO, but will also attenuate the synthesis of very long chain saturated, mono- and polyunsaturated fatty acids.

Elevated hepatic fatty acid elongase-5 activity corrects dietary fat-induced hyperglycemia in obese C57BL/6J mice.

Elevated hepatic fatty acid elongase-5 (Elovl5) activity lowers blood glucose in fasted chow-fed C57BL/6J mice. As high-fat diets induce hyperglycemia and suppress hepatic Elovl5 activity, we tested the hypothesis that elevated hepatic Elovl5 expression attenuates hyperglycemia in high-fat-diet-induced obese mice. Increasing hepatic Elovl5 activity by a recombinant adenoviral approach restored blood glucose and insulin, HOMA-IR, and glucose tolerance to normal values in obese mice. Elevated Elovl5 activity increased hepatic content of Elovl5 products (20:3,n-6, 22:4,n-6) and suppressed levels of enzymes (Pck1, G6Pc) and transcription factors (FoxO1 and PGC1alpha, but not CRTC2) involved in gluconeogenesis. Effects of Elovl5 on FoxO1 nuclear abundance correlated with increased phosphorylation of FoxO1, Akt, and the catalytic unit of PP2A, as well as a decline in cellular abundance of TRB3. Such changes are mechanistically linked to the regulation of FoxO1 nuclear abundance and gluconeogenesis. These results show that Elovl5 activity impacts the hepatic abundance and phosphorylation status of multiple proteins involved in gluconeogenesis. Our findings establish a link between fatty acid elongation and hepatic glucose metabolism and suggest a role for regulators of Elovl5 activity in the treatment of diet-induced hyperglycemia.