Empagliflozin protects mice against diet-induced obesity, insulin resistance and hepatic steatosis.

AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used in the treatment of type 2 diabetes, heart failure and chronic kidney disease. Their role in the prevention of diet-induced metabolic deteriorations, such as obesity, insulin resistance and fatty liver disease, has not been defined yet. In this study we set out to test whether empagliflozin prevents weight gain and metabolic dysfunction in a mouse model of diet-induced obesity and insulin resistance. METHODS: C57Bl/6 mice were fed a western-type diet supplemented with empagliflozin (WDE) or without empagliflozin (WD) for 10 weeks. A standard control diet (CD) without or with empagliflozin (CDE) was used to control for diet-specific effects. Metabolic phenotyping included assessment of body weight, food and water intake, body composition, hepatic energy metabolism, skeletal muscle mitochondria and measurement of insulin sensitivity using hyperinsulinaemic-euglycaemic clamps. RESULTS: Mice fed the WD were overweight, hyperglycaemic, hyperinsulinaemic and insulin resistant after 10 weeks. Supplementation of the WD with empagliflozin prevented these metabolic alterations. While water intake was significantly increased by empagliflozin supplementation, food intake was similar in WDE- and WD-fed mice. Adipose tissue depots measured by MRI were significantly smaller in WDE-fed mice than in WD-fed mice. Additionally, empagliflozin supplementation prevented significant steatosis found in WD-fed mice. Accordingly, hepatic insulin signalling was deteriorated in WD-fed mice but not in WDE-fed mice. Empagliflozin supplementation positively affected size and morphology of mitochondria in skeletal muscle in both CD- and WD-fed mice. CONCLUSIONS/INTERPRETATION: Empagliflozin protects mice from diet-induced weight gain, insulin resistance and hepatic steatosis in a preventative setting and improves muscle mitochondrial morphology independent of the type of diet.

COVID-19 fatality prediction in people with diabetes and prediabetes using a simple score upon hospital admission.

AIM: To assess predictors of in-hospital mortality in people with prediabetes and diabetes hospitalized for COVID-19 infection and to develop a risk score for identifying those at the greatest risk of a fatal outcome. MATERIALS AND METHODS: A combined prospective and retrospective, multicentre, cohort study was conducted at 10 sites in Austria in 247 people with diabetes or newly diagnosed prediabetes who were hospitalized with COVID-19. The primary outcome was in-hospital mortality and the predictor variables upon admission included clinical data, co-morbidities of diabetes or laboratory data. Logistic regression analyses were performed to identify significant predictors and to develop a risk score for in-hospital mortality. RESULTS: The mean age of people hospitalized (n = 238) for COVID-19 was 71.1 ± 12.9 years, 63.6% were males, 75.6% had type 2 diabetes, 4.6% had type 1 diabetes and 19.8% had prediabetes. The mean duration of hospital stay was 18 ± 16 days, 23.9% required ventilation therapy and 24.4% died in the hospital. The mortality rate in people with diabetes was numerically higher (26.7%) compared with those with prediabetes (14.9%) but without statistical significance (P = .128). A score including age, arterial occlusive disease, C-reactive protein, estimated glomerular filtration rate and aspartate aminotransferase levels at admission predicted in-hospital mortality with a C-statistic of 0.889 (95% CI: 0.837-0.941) and calibration of 1.000 (P = .909). CONCLUSIONS: The in-hospital mortality for COVID-19 was high in people with diabetes but not significantly different to the risk in people with prediabetes. A risk score using five routinely available patient variables showed excellent predictive performance for assessing in-hospital mortality.

Apolipoprotein A5 controls fructose-induced metabolic dysregulation in mice.

BACKGROUND AND AIMS: Western dietary habits are partially characterized by increased uptake of fructose, which contributes to metabolic dysregulation and associated liver diseases. For example, a diet enriched with fructose drives insulin resistance and non-alcoholic fatty liver disease (NAFLD). The molecular hubs that control fructose-induced metabolic dysregulation are poorly understood. Apolipoprotein A5 (apoA5) controls triglyceride metabolism with a putative role in hepatic lipid deposition. We explored apoA5 as a rheostat for fructose-induced hepatic and metabolic disease in mammals. METHODS AND RESULTS: ApoA5 knock out (-/-) and wildtype (wt) mice were fed with high fructose diet or standard diet for 10 weeks. Afterwards, we conducted a metabolic characterization by insulin tolerance test as well as oral glucose tolerance test. Additionally, hepatic lipid content as well as transcription patterns of key enzymes and transcription factors in glucose and lipid metabolism were evaluated. Despite comparable body weight, insulin sensitivity was significantly improved in high fructose diet fed apoA5 (-/-) when compared to wildtype mice on the same diet. In parallel, hepatic triglyceride content was significantly lower in apoA5 (-/-) mice than in wt mice. No difference was seen between apoA5 (-/-) and wt mice on a standard diet. CONCLUSION: ApoA5 is involved in fructose-induced metabolic dysregulation and associated hepatic steatosis suggesting that apoA5 may be a novel target to treat metabolic diseases.

Dipeptidyl peptidase-4 impairs insulin signaling and promotes lipid accumulation in hepatocytes.

Dipeptidyl-peptidase 4 [DPP-4) has evolved into an important target in diabetes therapy due to its role in incretin hormone metabolism. In contrast to its systemic effects, cellular functions of membranous DPP-4 are less clear. Here we studied the role of DPP-4 in hepatic energy metabolism. In order to distinguish systemic from cellular effects we established a cell culture model of DPP-4 knockdown in human hepatoma cell line HepG2. DPP-4 suppression was associated with increased basal glycogen content due to enhanced insulin signaling as shown by increased phosphorylation of insulin-receptor substrate 1 (IRS-1), protein kinase B/Akt and mitogen-activated protein kinases (MAPK)/ERK, respectively. Additionally, glucose-6-phosphatase cDNA expression was significantly decreased in DPP-4 deficiency. Reduced triglyceride content in DPP-4 knockdown cells was paralleled by enhanced expressions of peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase -1 (CPT-1) while sterol regulatory element-binding protein 1c (SREBP-1c) expression was significantly decreased. Our data suggest that hepatic DPP-4 induces a selective pathway of insulin resistance with reduced glycogen storage, enhanced glucose output and increased lipid accumulation in the liver. Hepatic DPP-4 might be a novel target in fatty liver disease in patients with glucose intolerance.

[Hospital diabetes management (Update 2023)]. / Diabetesmanagement im Krankenhaus (Update 2023).

This position statement presents the recommendations of the Austrian Diabetes Association for diabetes management of adult patients during inpatient stay. It is based on the current evidence with respect to blood glucose targets, insulin therapy and treatment with oral/injectable antidiabetic drugs during inpatient hospitalization. Additionally, special circumstances such as intravenous insulin therapy, concomitant therapy with glucocorticoids and use of diabetes technology during hospitalization are discussed.

[Prevention and management of postinterventional weight regain]. / Prävention und Management von postinterventioneller Gewichtszunahme.

Decreasing levels of patient motivation or compliance are far from being the only causes of postinterventional weight regain after lifestyle, psychological, pharmacological and surgical interventions. Weight regain originates from a complex and individually varying set of central and peripheral mechanisms, with the overall purpose of increasing food intake by both stimulating hunger and reducing satiety (mediated by gastrointestinal hormones) and decreasing the body's energy demands (via metabolic adaption). These mechanisms counteract any attempts to reduce or maintain body weight in today's increasingly prevalent adipogenic environments. The knowledge about the biological mechanisms of body weight regulation should be taken into consideration when planning treatment programs for long-term weight reduction, including follow-up treatment for the prevention and individualized treatment of postinterventional weight regain. Therapeutic measures as well as the frequency of medical follow-ups should be based on the extent of weight regain.

Alterations of hepatic energy metabolism in murine models of obesity, diabetes and fatty liver diseases.

BACKGROUND: Disturbed hepatic energy metabolism contributes to non-alcoholic fatty liver (NAFLD), but the development of changes over time and obesity- or diabetes-related mechanisms remained unclear. METHODS: Two-day old male C57BL/6j mice received streptozotocin (STZ) or placebo (PLC) and then high-fat (HFD) or regular chow diet (RCD) from week 4 (W4) to either W8 or W16, yielding control [CTRL = PLC + RCD], diabetes [DIAB = STZ + RCD], obesity [OBES = PLC + HFD] and diabetes-related non-alcoholic steatohepatitis [NASH = STZ + HFD] models. Mitochondrial respiration was measured by high-resolution respirometry and insulin-sensitive glucose metabolism by hyperinsulinemic-euglycemic clamps with stable isotope dilution. FINDINGS: NASH showed higher steatosis and NAFLD activity already at W8 and liver fibrosis at W16 (all p < 0.01 vs CTRL). Ballooning was increased in DIAB and NASH at W16 (p < 0.01 vs CTRL). At W16, insulin sensitivity was 47%, 58% and 75% lower in DIAB, NASH and OBES (p < 0.001 vs CTRL). Hepatic uncoupled fatty acid oxidation (FAO)-associated respiration was reduced in OBES at W8, but doubled in DIAB and NASH at W16 (p < 0.01 vs CTRL) and correlated with biomarkers of unfolded protein response (UPR), oxidative stress and hepatic expression of certain enzymes (acetyl-CoA carboxylase 2, Acc2; carnitine palmitoyltransferase I, Cpt1a). Tricarboxylic acid cycle (TCA)-driven respiration was lower in OBES at W8 and doubled in DIAB at W16 (p < 0.0001 vs CTRL), which positively correlated with expression of genes related to lipolysis. INTERPRETATION: Hepatic mitochondria adapt to various metabolic challenges with increasing FAO-driven respiration, which is linked to dysfunctional UPR, systemic oxidative stress, insulin resistance and altered lipid metabolism. In a diabetes model, higher TCA-linked respiration reflected mitochondrial adaptation to greater hepatic lipid turnover. FUNDING: Funding bodies that contributed to this study were listed in the acknowledgements section.

[Other specific types of diabetes and exocrine pancreatic insufficiency (update 2023)]. / Andere spezifische Diabetesformen und exokrine Pankreasinsuffizienz (Update 2023).

The heterogenous category "specific types of diabetes due to other causes" encompasses disturbances in glucose metabolism due to other endocrine disorders such as acromegaly or hypercortisolism, drug-induced diabetes (e.g. antipsychotic medications, glucocorticoids, immunosuppressive agents, highly active antiretroviral therapy (HAART), checkpoint inhibitors), genetic forms of diabetes (e.g. Maturity Onset Diabetes of the Young (MODY), neonatal diabetes, Down­, Klinefelter- and Turner Syndrome), pancreatogenic diabetes (e.g. postoperatively, pancreatitis, pancreatic cancer, haemochromatosis, cystic fibrosis), and some rare autoimmune or infectious forms of diabetes. Diagnosis of specific diabetes types might influence therapeutic considerations. Exocrine pancreatic insufficiency is not only found in patients with pancreatogenic diabetes but is also frequently seen in type 1 and long-standing type 2 diabetes.

[Antihyperglycemic treatment guidelines for diabetes mellitus type 2 (Update 2023)]. / Antihyperglykämische Therapie bei Diabetes mellitus Typ 2 (Update 2023).

Hyperglycemia significantly contributes to complications in patients with diabetes mellitus. While lifestyle interventions remain cornerstones of disease prevention and treatment, most patients with type 2 diabetes will eventually require pharmacotherapy for glycemic control. The definition of individual targets regarding optimal therapeutic efficacy and safety as well as cardiovascular effects is of great importance. In this guideline we present the most current evidence-based best clinical practice data for healthcare professionals.

[Overweight and obesity in adults: general principles of treatment and conservative management]. / Übergewicht und Adipositas bei Erwachsenen: allgemeine Behandlungsgrundsätze und konservatives Management.

The prevalence of overweight and obesity is steadily increasing in Austria as well as internationally. Obesity in particular is associated with multiple health risks, comorbidities, functional disability, and social stigma. Obesity is an independent, complex, chronic disease and should be treated as such by a multidisciplinary team of appropriately qualified personnel. In addition to recent international guidelines, this consensus paper outlines the overall principles of the management of overweight and obesity and provides guidance for the diagnosis and conservative treatment, focusing on lifestyle modifications and pharmacotherapy. Using the "5A" framework of behavioral health intervention, guidelines for a structured, pragmatic, and patient-centered medical care of adults with overweight or obesity are presented.

Changing the dietary composition improves inflammation but not adipocyte thermogenesis in diet-induced obese mice.

Pronounced weight loss was shown to improve adipocyte dysfunction and insulin sensitivity in obese subjects. While bariatric surgery is frequently accompanied by adverse side effects, weight loss due to caloric restriction is often followed by weight regain. Here we aimed to determine whether switching the diet from a metabolically harmful Western type diet to a balanced standard diet is sufficient to reverse adipocyte dysfunction in diet-induced obese mice. Male C57BL/6 mice were fed a Western diet for 10 weeks and afterwards switched to a standard diet for eight more weeks (WD/SD mice) or continued to be fed a Western diet (WD/WD mice) ad libitum. Mice fed SD for 18 weeks served as control group (SD/SD). Insulin sensitivity was similar in WD/SD and SD/SD mice despite increased body weight in WD/SD mice. Beiging markers Ucp-1, Cidea and Cox8b were drastically reduced in subcutaneous adipose tissue of WD/SD mice when compared with SD/SD mice. Also, in brown adipose tissue morphologic features and markers of thermogenesis were still altered in both WD/SD and WD/WD mice. However, adipocyte size, Hif1α and macrophage infiltration were significantly lower in both, brown and white adipose tissues of WD/SD compared to WD/WD mice and additionally, a shift toward anti-inflammatory M2 phenotype was found in WD/SD mice only. In conclusion our data suggest that switching the diet is sufficient to improve adipose tissue inflammation, while western diet negatively affects thermogenic capacity of brown adipose tissue, and inhibits beiging of white adipose tissue in the long-term.

Biomarkers Predictive for In-Hospital Mortality in Patients with Diabetes Mellitus and Prediabetes Hospitalized for COVID-19 in Austria: An Analysis of COVID-19 in Diabetes Registry.

BACKGROUND: This study assessed the predictive performance of inflammatory, hepatic, coagulation, and cardiac biomarkers in patients with prediabetes and diabetes mellitus hospitalized for COVID-19 in Austria. METHODS: This was an analysis of a multicenter cohort study of 747 patients with diabetes mellitus or prediabetes hospitalized for COVID-19 in 11 hospitals in Austria. The primary outcome of this study was in-hospital mortality. The predictor variables included demographic characteristics, clinical parameters, comorbidities, use of medication, disease severity, and laboratory measurements of biomarkers. The association between biomarkers and in-hospital mortality was assessed using simple and multiple logistic regression analyses. The predictive performance of biomarkers was assessed using discrimination and calibration. RESULTS: In our analysis, 70.8% had type 2 diabetes mellitus, 5.8% had type 1 diabetes mellitus, 14.9% had prediabetes, and 8.6% had other types of diabetes mellitus. The mean age was 70.3 ± 13.3 years, and 69.3% of patients were men. A total of 19.0% of patients died in the hospital. In multiple logistic regression analysis, LDH, CRP, IL-6, PCT, AST-ALT ratio, NT-proBNP, and Troponin T were significantly associated with in-hospital mortality. The discrimination of NT-proBNP was 74%, and that of Troponin T was 81%. The calibration of NT-proBNP was adequate (p = 0.302), while it was inadequate for Troponin T (p = 0.010). CONCLUSION: Troponin T showed excellent predictive performance, while NT-proBNP showed good predictive performance for assessing in-hospital mortality in patients with diabetes mellitus hospitalized with COVID-19. Therefore, these cardiac biomarkers may be used for prognostication of COVID-19 patients.

Effect of weight loss on serum pigment epithelium-derived factor levels.

BACKGROUND: Cumulating evidence suggests that the broadly acting neurotrophic pigment epithelium-derived factor is associated with visceral adiposity, the metabolic syndrome, diabetes and exerts beneficial effects on atherosclerosis. To further elucidate the relationship between pigment epithelium-derived factor and metabolic perturbations characteristic of obesity, we examined the effect of pronounced weight loss on serum levels of pigment epithelium-derived factor. MATERIALS AND METHODS: Thirty-six severely obese adults were examined before and 18 months after bariatric surgery. Abdominal fat distribution was determined by ultrasound, metabolic parameters by standard methods, pro-inflammatory biomarkers and serum pigment epithelium-derived factor levels by enzyme-linked immunosorbent assay. RESULTS: Bariatric surgery resulted in a mean body mass index (BMI) reduction of 9·0 ± 5·0 kg m(-2) and concomitant improvements in glucose homoeostasis and lipid profile. Pigment epithelium-derived factor serum levels decreased from a median 11·0 µg mL(-1) (interquartile range: 3·8) to 9·2 µg mL(-1) (interquartile range: 4·5) (P < 0·0001). In univariate analysis, relative change in pigment epithelium-derived factor levels was significantly associated with change in weight, BMI, fat mass, visceral fat diameter, insulin, homoeostasis model for insulin resistance, triglyceride and leptin levels (all r > 0·370, P < 0·05). No associations were observed for C-reactive protein, interleukin-6 or tumour necrosis factor alpha. After adjustment for age, sex and smoking status, associations remained significant. CONCLUSIONS: The beneficial effects of bariatric surgery-induced pronounced weight loss on glucose homoeostasis may partially be attributable to visceral adipose tissue reduction and concomitantly decreasing pigment epithelium-derived factor concentrations.

[Psychotropic drugs and diabetes]. / Psychopharmaka und Diabetes.

Psychotropic drugs, such as antipsychotics and antidepressants, are widely used substances which can display marked metabolic side effects. Psychiatric patients display increased morbidity and mortality which, besides disease specific factors, may be attributed to metabolic side effects of psychotropic drugs. Commonly observed side effects of antipsychotics are weight gain as well as disturbances in glucose and lipid metabolism. Additionally, antipsychotics have been shown to increase diabetes risk. Also, the use of some of the antidepressant substances is associated with an increased diabetes risk. However, large inter-substance variations have been observed. Conversely, diabetics have an increased risk of depression. Metabolic side effects of psychotropic drugs pose a serious impairment for psychiatric patients and their management can play a pivotal role in therapeutic compliance and success. This review aims to give an overview of metabolic side effects of commonly used psychotic drugs and to give an insight into possible underlying mechanisms.

COVID-19 In-Hospital Mortality in People with Diabetes Is Driven by Comorbidities and Age-Propensity Score-Matched Analysis of Austrian National Public Health Institute Data.

BACKGROUND: It is a matter of debate whether diabetes alone or its associated comorbidities are responsible for severe COVID-19 outcomes. This study assessed the impact of diabetes on intensive care unit (ICU) admission and in-hospital mortality in hospitalized COVID-19 patients. METHODS: A retrospective analysis was performed on a countrywide cohort of 40,632 COVID-19 patients hospitalized between March 2020 and March 2021. Data were provided by the Austrian data platform. The association of diabetes with outcomes was assessed using unmatched and propensity-score matched (PSM) logistic regression. RESULTS: 12.2% of patients had diabetes, 14.5% were admitted to the ICU, and 16.2% died in the hospital. Unmatched logistic regression analysis showed a significant association of diabetes (odds ratio [OR]: 1.24, 95% confidence interval [CI]: 1.15-1.34, p < 0.001) with in-hospital mortality, whereas PSM analysis showed no significant association of diabetes with in-hospital mortality (OR: 1.08, 95%CI: 0.97-1.19, p = 0.146). Diabetes was associated with higher odds of ICU admissions in both unmatched (OR: 1.36, 95%CI: 1.25-1.47, p < 0.001) and PSM analysis (OR: 1.15, 95%CI: 1.04-1.28, p = 0.009). CONCLUSIONS: People with diabetes were more likely to be admitted to ICU compared to those without diabetes. However, advanced age and comorbidities rather than diabetes itself were associated with increased in-hospital mortality in COVID-19 patients.

Cardioprotective effects of short-term empagliflozin treatment in db/db mice.

Sodium glucose transporter (SGLT)-2 inhibitors have consistently shown cardioprotective effects independent of the glycemic status of treated patients. In this study we aimed to investigate underlying mechanisms of short-term empagliflozin treatment in a mouse model of type II diabetes. Male db/db mice were fed a western type diet with or without enrichment with empagliflozin for 7 days. While glucose tolerance was significantly improved in empagliflozin treated mice, body weight and fasting insulin levels were comparable in both groups. Cardiac insulin signaling activity indicated by reduced proteinkinase B (AKT) phosphorylation was significantly decreased in the empagliflozin treated group. Remarkably, mitochondrial mass estimated by citrate synthase activity was significantly elevated in empagliflozin treated mice. Accordingly, mitochondrial morphology was significantly altered upon treatment with empagliflozin as analysed by transmission electron microscopy. Additionally, short-term empagliflozin therapy was associated with a changed cardiac tissue cytokine expression in favor of an anti-inflammatory pattern. Our data suggest that early cardioprotection in empagliflozin treated mice is independent of a reduction in body weight or hyperinsulinemia. Ameliorated mitochondrial ultrastructure, attenuated cardiac insulin signaling and diminished cardiac inflammation might contribute to the cardioprotective effects of empagliflozin.

Metabolic effects of reduced growth hormone action in fatty liver disease.

BACKGROUND: Adult growth hormone (GH) deficiency is associated with fatty liver disease and shows several features of the metabolic syndrome. Vice versa obesity is characterized as a state of low GH function. Here, we aimed to define the role of hepatic GH signaling and its metabolic consequences in non-alcoholic fatty liver disease. METHODS: In humans, GHR and IGF-1 levels were determined in liver samples of 29 obese patients with non-alcoholic steatohepatitis (NASH) or simple steatosis. Cellular effects of GH on insulin signaling were investigated in GH receptor (GHR) knockdown HepG2 cells. RESULTS: Hepatic IGF-1 expression levels reflecting GH action were significantly lower and fasting glucose concentrations higher in patients with NASH than in patients with simple steatosis. GHR knockdown in hepatocytes resulted in a scenario of high glucose output displayed by reduced glycogen content, increased gluconeogenesis and diminished insulin signaling. CONCLUSIONS: Our data suggest that GH signaling in the liver is diminished in patients with NASH and associated with deteriorated hepatic insulin sensitivity and metabolic activity. Reduced hepatic GH action might contribute to insulin resistance in obese patients with NASH.

Circulating Wnt inhibitory factor 1 levels are associated with development of cardiovascular disease.

BACKGROUND AND AIMS: Wnt signaling is involved in atherosclerotic plaque formation directly and indirectly by modulating cardiovascular risk factors. We investigated whether circulating concentrations of Wnt inhibitors are associated with cardiovascular events in subjects with intermediate cardiovascular risk. METHODS: 904 non-diabetic subjects participating in the SAPHIR study were assessed. In the SAPHIR study, middle-aged women without overt atherosclerotic disease at study entry were followed up for 10 years. 88 patients of our study cohort developed cardiovascular disease at follow-up (CVD group). Subjects of the CVD group were 1:2 case-control matched for age, sex, BMI and smoking behavior with subjects without overt cardiovascular disease after a 10 year-follow-up (control group). 18 patients of the CVD group and 19 subjects of the control group were retrospectively excluded due to fulfilling exclusion criteria. Baseline circulating sclerostin, dickkopf (DKK)-1, secreted frizzled-related protein (SFRP)-1 and Wnt inhibitory factor (WIF)-1 levels were assessed by ELISA. RESULTS: Baseline systemic SFRP-1 and WIF-1 levels were significantly higher in patients with cardiovascular events (n = 70) when compared to healthy controls (n = 157) while DKK-1 and sclerostin levels were similar in both groups. Logistic regression analysis revealed WIF-1 as a significant predictor of future cardiovascular events. CONCLUSIONS: Our data suggest that increased SFRP-1 and WIF-1 levels precede the development of symptomatic atherosclerotic disease. Assessment of systemic WIF-1 levels, which turned out to be independently associated with CVD, might help to early identify patients at intermediate cardiovascular risk.

Fat-enriched rather than high-fructose diets promote whitening of adipose tissue in a sex-dependent manner.

Adipose tissue is a critical regulator of energy metabolism and an effector organ of excessive caloric intake. We studied the effects of high-fructose (HFruD), high-fat (HFD) and mixed high-sucrose and high-fat diet (HFHSD) on adipocyte morphology and biology and consecutive metabolic effects in male and female C57BL/6 mice. Forty male and 40 female mice were randomly assigned to one of four dietary groups and fed for 10 weeks ad libitum. After 10 weeks of feeding, mice were analyzed in regard to glucose metabolism, insulin sensitivity and alteration in adipocyte morphology and function. Weight gain and diminished insulin sensitivity in HFD- and HFHSD-fed mice were accompanied by increased adipocyte size and a shift in size distribution towards larger adipocytes in all mice. The latter effect was also found but less pronounced in HFruD-fed mice, while insulin sensitivity and body weight remained unaffected. In male mice, expansion of white adipocytes along with decreased uncoupling protein 1 (UCP-1) expression and alterations of mitochondrial biogenesis was found after HFD and HFHSD feeding, while in female mice, UCP-1 expression was also reduced in the HFruD dietary group. Diet-induced cellular alterations were less pronounced in female mice. Our data demonstrate that high-fat rather than high fructose consumption drives metabolically disadvantageous alterations of adipocyte differentiation involving whitening and insulin resistance in a sex-dependent manner with most deleterious effects seen upon administration of combined sucrose and fat-enriched diet in male mice.

Mechanisms of intrahepatic triglyceride accumulation.

Hepatic steatosis defined as lipid accumulation in hepatocytes is very frequently found in adults and obese adolescents in the Western World. Etiologically, obesity and associated insulin resistance or excess alcohol intake are the most frequent causes of hepatic steatosis. However, steatosis also often occurs with chronic hepatitis C virus (HCV) infection and is also found in rare but potentially life-threatening liver diseases of pregnancy. Clinical significance and outcome of hepatic triglyceride accumulation are highly dependent on etiology and histological pattern of steatosis. This review summarizes current concepts of pathophysiology of common causes of hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease, chronic HCV infections, drug-induced forms of hepatic steatosis, and acute fatty liver of pregnancy. Regarding the pathophysiology of NAFLD, this work focuses on the close correlation between insulin resistance and hepatic triglyceride accumulation, highlighting the potential harmful effects of systemic insulin resistance on hepatic metabolism of fatty acids on the one side and the role of lipid intermediates on insulin signalling on the other side. Current studies on lipid droplet morphogenesis have identified novel candidate proteins and enzymes in NAFLD.