Lipolysis, and Not Hepatic Lipogenesis, Is the Primary Modulator of Triglyceride Levels in Streptozotocin-Induced Diabetic Mice

Willecke, Florian; Scerbo, Diego; Nagareddy, Prabhakara R; Obunike, Joseph C.; Barrett, Tessa J.; Abdillahi, Mariane; Trent, Chad M.; Huggins, Lesley Ann; Fisher, Edward A.; Drosatos, Konstantinos; Goldberg, Ira J.

doi:10.1161/atvbaha.114.304615

Cited by 41 publications

(56 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Lipids were extracted according to the method of Willecke et al with minor modifications [16]. Heart and liver tissue was homogenized in PBS (approximately 50 mg tissue in 1 ml PBS) using stainless steel beads for 5 min at 4 °C in a bead beater homogenizer.…”

Section: Methodsmentioning

confidence: 99%

A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice

Nilsson¹,

Ericsson²,

Joibari³

et al. 2016

Nutr Metab (Lond)

View full text Add to dashboard Cite

BackgroundExcess body fat is a major health issue and a risk factor for the development of numerous chronic diseases. Low-carbohydrate diets like the Atkins Diet are popular for rapid weight loss, but the long-term consequences remain the subject of debate. The Scandinavian low-carbohydrate high-fat (LCHF) diet, which has been popular in Scandinavian countries for about a decade, has very low carbohydrate content (~5 E %) but is rich in fat and includes a high proportion of saturated fatty acids. Here we investigated the metabolic and physiological consequences of a diet with a macronutrient composition similar to the Scandinavian LCHF diet and its effects on the organs, tissues, and metabolism of weight stable mice.MethodsFemale C57BL/6J mice were iso-energetically pair-fed for 4 weeks with standard chow or a LCHF diet. We measured body composition using echo MRI and the aerobic capacity before and after 2 and 4 weeks on diet. Cardiac function was assessed by echocardiography before and after 4 weeks on diet. The metabolic rate was measured by indirect calorimetry the fourth week of the diet. Mice were sacrificed after 4 weeks and the organ weight, triglyceride levels, and blood chemistry were analyzed, and the expression of key ketogenic, metabolic, hormonal, and inflammation genes were measured in the heart, liver, and adipose tissue depots of the mice using real-time PCR.ResultsThe increase in body weight of mice fed a LCHF diet was similar to that in controls. However, while control mice maintained their body composition throughout the study, LCHF mice gained fat mass at the expense of lean mass after 2 weeks. The LCHF diet increased cardiac triglyceride content, impaired cardiac function, and reduced aerobic capacity. It also induced pronounced alterations in gene expression and substrate metabolism, indicating a unique metabolic state.ConclusionsPair-fed mice eating LCHF increased their percentage of body fat at the expense of lean mass already after 2 weeks, and after 4 weeks the function of the heart deteriorated. These findings highlight the urgent need to investigate the effects of a LCHF diet on health parameters in humans.

show abstract

Section: Methodsmentioning

confidence: 99%

A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice

Nilsson¹,

Ericsson²,

Joibari³

et al. 2016

Nutr Metab (Lond)

View full text Add to dashboard Cite

show abstract

“…Insulin deficiency may also suppress adipose LpL expression (108), which could further compound the hypertriglyceridemia seen in diabetic states. Consistent with this hypothesis, mice overexpressing skeletal muscle LpL were protected from the hypertriglyceridemia seen with streptozotocin treatment, demonstrating that the creation of a tissue depot for lipids could alter lipid storage and prevent hyperlipidemia (108).…”

Section: Adipose Insulin Resistancementioning

confidence: 99%

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

Samuel¹,

Shulman²

2016

Journal of Clinical Investigation

1,052

819

View full text Add to dashboard Cite

In most natural habitats, calorie availability is scarce and unpredictable, necessitating the evolution of systems for the efficient storage and utilization of energy. But in our modern, mechanized society, caloric demands are minimized, while highly palatable, calorie-dense foods and beverages are readily available. These changes have fostered the current pandemic of obesity and comorbid conditions of nonalcoholic fatty liver disease (NAFLD), atherosclerosis, and type 2 diabetes (T2D). Insulin resistance is a common feature of all these diseases, and much effort has been invested in delineating the pathogenesis of insulin resistance. We will first review the role of insulin and nutrients (specifically glucose and fatty acids) in nutrient storage ( Figure 1) and then use this framework to explore the various defects that give rise to insulin resistance and T2D (Figure 2). Postprandial hepatic glucose and lipid metabolismThe simple act of eating rapidly shifts hepatic glucose metabolism from glucose production to glucose storage, a complex transition regulated by multiple factors including nutrients, alterations in pancreatic and enteric hormones, and neural regulation. Insulin is a crucial regulator of this transition, primarily by activating glycogen synthase (1). The importance of insulin is seen in patients with type 1 diabetes (T1D), who only synthesize one-third the amount of hepatic glycogen as control subjects after a mixed meal (2). Yet, hyperinsulinemia, in the absence of hyperglycemia, promotes hepatic glycogen cycling with minimal net hepatic glycogen synthesis (1). And hyperglycemia, without hyperinsulinemia, inhibits hepatic glycogenolysis via glucose-mediated inhibition of glycogen phosphorylase (3), with minimal net hepatic glycogen synthesis (1). The combination of hyperinsulinemia and hyperglycemia maximizes net hepatic glycogen synthesis (1). Other nutrients further optimize net hepatic glycogen synthesis, such as activation of glucokinase by catalytic quantities of fructose (4).Hepatic insulin action requires a coordinated relay of intracellular signals (Figure 1 and ref. 5). Insulin activates the insulin receptor tyrosine kinase (IRTK), with subsequent activation of kinases including 3-phosphoinositide-dependent kinase-1 (PDK1) and mTORC2 (6), which converge on Akt phosphorylation (6-8). The pattern of insulin delivery may also impact Akt phosphorylation, with pulsatile portal delivery (which better mimics physiology) leading to greater activation than continuous, fixed insulin delivery (9). Activation of Akt is the integral result of multiple inputs to regulate hepatic glucose and lipid metabolism. This model has been used to explain how insulin suppresses hepatic glucose production via (i) lowering expression of gluconeogenic enzymes via phosphorylation and nuclear exclusion of FOXO1 and (ii) inactivation of glycogen synthase kinase 3β (GSK3β), which permits the activation of glycogen synthase.Recent studies challenge the primacy of the Akt/GSK3β/ glycogen synthase branch in the regulation ...

show abstract

“…194 Interestingly, insulin deficiency in mice leads to increased triglyceride levels and defective removal of postprandial triglycerides, indicating that significant hypertriglyceridemia in insulindependent diabetes is primarily because of changes in lipolysis and not changes in hepatic insulin signaling. 195 LPL is also regulated also by several apoproteins including apoCII, apoCIII, angiopoietin-like 3 (ANGPTL-3) and ANGPTL-4. 196 Much interest has focused on apoCIII since it is elevated in type 2 diabetic subjects and correlates with serum triglyceride levels (Figure 6).…”

Section: Regulation Of Trl Clearancementioning

confidence: 99%

New insights into the pathophysiology of dyslipidemia in type 2 diabetes

2015

View full text Add to dashboard Cite

Lipolysis, and Not Hepatic Lipogenesis, Is the Primary Modulator of Triglyceride Levels in Streptozotocin-Induced Diabetic Mice

Cited by 41 publications

References 67 publications

A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice

A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

New insights into the pathophysiology of dyslipidemia in type 2 diabetes

Contact Info

Product

Resources

About