Faculty Opinions recommendation of Short-term weight loss attenuates local tissue inflammation and improves insulin sensitivity without affecting adipose inflammation in obese mice.

Non-alcoholic fatty liver disease (NAFLD) has a positive correlation with obesity, insulin resistance and type 2 diabetes mellitus (T2D). The aerobic training is an important tool in combating NAFLD. However, no studies have demonstrated the molecular effects of short-term strength training on the accumulation of hepatic fat in obese mice. This study aimed to investigate the effects of short-term strength training on the mechanisms of oxidation and lipid synthesis in the liver of obese mice. The short duration protocol was used to avoid changing the amount of adipose tissue. Swiss mice were separated into three groups: lean control (CTL), sedentary obese (OB) and strength training obese (STO). The obese groups were fed a high-fat diet (HFD) and the STO group performed the strength training protocol 1 session/day for 15 days. The short-term strength training reduced hepatic fat accumulation, increasing hepatic insulin sensitivity and controlling hepatic glucose production. The obese animals increased the mRNA of lipogenic genes Fasn and Scd1 and reduced the oxidative genes Cpt1a and Ppara. On the other hand, the STO group presented the opposite results. Finally, the obese animals presented higher levels of lipogenic proteins (ACC and FAS) and proinflammatory cytokines (TNF-α and IL-1β), but the short-term strength training was efficient in reducing this condition, regardless of body weight loss. In conclusion, there was a reduction of obesity-related hepatic lipogenesis and inflammation after short-term strength training, independent of weight loss, leading to improvements in hepatic insulin sensitivity and glycemic homeostasis in obese mice. Key points: (1) Short-term strength training (STST) reduced fat accumulation and inflammation in the liver; (2) Hepatic insulin sensitivity and HPG control were increased with STST; (3) The content and activity of ACC and content of FAS were reduced with STST; (4) STST improved hepatic fat accumulation and glycemic homeostasis; (5) STST effects were observed independently of body weight change.

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Short-term weight loss attenuates local tissue inflammation and improves insulin sensitivity without affecting adipose inflammation in obese mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00462.2012 ◽

2013 ◽

Vol 304 (9) ◽

pp. E964-E976 ◽

Cited By ~ 21

Author(s):

Dae Young Jung ◽

Hwi Jin Ko ◽

Eben I. Lichtman ◽

Eunjung Lee ◽

Elizabeth Lawton ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Glucose Homeostasis ◽

Local Inflammation ◽

Lipid Levels ◽

Short Term ◽

Tissue Inflammation

Obesity is a major cause of insulin resistance, and weight loss is shown to improve glucose homeostasis. But the underlying mechanism and the role of inflammation remain unclear. Male C57BL/6 mice were fed a high-fat diet (HFD) for 12 wk. After HFD, weight loss was induced by changing to a low-fat diet (LFD) or exercise with continuous HFD. The weight loss effects on energy balance and insulin sensitivity were determined using metabolic cages and hyperinsulinemic euglycemic clamps in awake mice. Diet and exercise intervention for 3 wk caused a modest weight loss and improved glucose homeostasis. Weight loss dramatically reduced local inflammation in skeletal muscle, liver, and heart but not in adipose tissue. Exercise-mediated weight loss increased muscle glucose metabolism without affecting Akt phosphorylation or lipid levels. LFD-mediated weight loss reduced lipid levels and improved insulin sensitivity selectively in liver. Both weight loss interventions improved cardiac glucose metabolism. These results demonstrate that a short-term weight loss with exercise or diet intervention attenuates obesity-induced local inflammation and selectively improves insulin sensitivity in skeletal muscle and liver. Our findings suggest that local factors, not adipose tissue inflammation, are involved in the beneficial effects of weight loss on glucose homeostasis.

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Inherent insulin sensitivity is a major determinant of multimeric adiponectin responsiveness to short-term weight loss in extreme obesity

Scientific Reports ◽

10.1038/srep05803 ◽

2014 ◽

Vol 4 (1) ◽

Cited By ~ 8

Author(s):

Stefania Mai ◽

Gillian E. Walker ◽

Amelia Brunani ◽

Gabriele Guzzaloni ◽

Glenda Grossi ◽

...

Keyword(s):

Weight Loss ◽

Insulin Sensitivity ◽

Major Determinant ◽

Extreme Obesity ◽

Short Term

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Myeloid-specific deletion of Zfp36 protects against insulin resistance and fatty liver in diet-induced obese mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00224.2017 ◽

2018 ◽

Vol 315 (4) ◽

pp. E676-E693 ◽

Cited By ~ 2

Author(s):

Valentina Caracciolo ◽

Jeanette Young ◽

Donna Gonzales ◽

Yingchun Ni ◽

Stephen J. Flowers ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Mrna Expression ◽

Zinc Finger Protein ◽

Inflammatory Responses ◽

Adipose Tissue Inflammation ◽

Obese Mice ◽

Tissue Inflammation ◽

Mrna Binding

Obesity is associated with adipose tissue inflammation that contributes to insulin resistance. Zinc finger protein 36 (Zfp36) is an mRNA-binding protein that reduces inflammation by binding to cytokine transcripts and promoting their degradation. We hypothesized that myeloid-specific deficiency of Zfp36 would lead to increased adipose tissue inflammation and reduced insulin sensitivity in diet-induced obese mice. As expected, wild-type (Control) mice became obese and diabetic on a high-fat diet, and obese mice with myeloid-specific loss of Zfp36 [knockout (KO)] demonstrated increased adipose tissue and liver cytokine mRNA expression compared with Control mice. Unexpectedly, in glucose tolerance testing and hyperinsulinemic-euglycemic clamp studies, myeloid Zfp36 KO mice demonstrated improved insulin sensitivity compared with Control mice. Obese KO and Control mice had similar macrophage infiltration of the adipose depots and similar peripheral cytokine levels, but lean and obese KO mice demonstrated increased Kupffer cell (KC; the hepatic macrophage)-expressed Mac2 compared with lean Control mice. Insulin resistance in obese Control mice was associated with enhanced Zfp36 expression in KCs. Compared with Control mice, KO mice demonstrated increased hepatic mRNA expression of a multitude of classical (M1) inflammatory cytokines/chemokines, and this M1-inflammatory hepatic milieu was associated with enhanced nuclear localization of IKKβ and the p65 subunit of NF-κB. Our data confirm the important role of innate immune cells in regulating hepatic insulin sensitivity and lipid metabolism, challenge-prevailing models in which M1 inflammatory responses predict insulin resistance, and indicate that myeloid-expressed Zfp36 modulates the response to insulin in mice.

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Short-term Ketogenic Diet Induces a Molecular Response that is Distinct from Dietary Protein Restriction

10.1101/2021.12.19.473355 ◽

2021 ◽

Author(s):

Krystle Kalafut ◽

Sarah J Mitchell ◽

Michael R MacArthur ◽

James R Mitchell

Keyword(s):

Weight Loss ◽

Insulin Sensitivity ◽

Protein Content ◽

Ketogenic Diet ◽

Dietary Protein ◽

Control Diet ◽

Protein Restriction ◽

Short Term ◽

Dietary Protein Restriction ◽

Ketogenic Diets

There is increasing interest in utilizing short-term dietary interventions in the contexts of cancer, surgical stress and metabolic disease. These short-term diets may be more feasible than extended interventions and may be designed to complement existing therapies. In particular, the high-fat, low-carbohydrate ketogenic diet (KD), traditionally used to treat epilepsy, has gained popularity as a potential strategy for weight loss and improved metabolic health. In mice, long-term KD improves insulin sensitivity and extends lifespan and healthspan. Dietary protein restriction (PR) causes increased energy expenditure, weight loss and improved glucose homeostasis. Since KD is inherently a low-protein diet (10% of calories from protein vs. 20% in control diet), here we evaluated the potential for mechanistic overlap between PR and KD via activation of a PR response. Mice were fed control, protein-free (PF), or one of four ketogenic diets with varying protein content for 8 days. PF and KD diets both decreased body weight, fat mass, and liver weights, and reduced fasting glucose and insulin levels, compared to mice fed the control diet. However, PF and KD differed with respect to insulin tolerance and hepatic insulin sensitivity, which were increased in PF-fed mice and impaired in KD-fed mice relative to controls. Furthermore, contrary to the PF-fed mice, mice fed ketogenic diets containing at least 5% protein did not increase hepatic Fgf21 or brown adipose Ucp1 expression. Interestingly, mice fed KD lacking protein demonstrated greater elevations in hepatic Fgf21 than mice fed a low-fat PF diet. To further elucidate potential mechanistic differences between PF and KD diets and the interplay between dietary protein and carbohydrate restriction, we conducted RNA-seq analysis on livers from mice fed each of the six diets and identified distinct gene sets which respond to dietary protein content, dietary fat content, and ketogenesis. We conclude that KD with 10% of energy from protein does not induce a protein restriction response, and that the overlapping metabolic benefits of KD and PF diets occur via distinct underlying mechanisms.

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Two-Week Isocaloric Time-Restricted Feeding Decreases Liver Inflammation without Significant Weight Loss in Obese Mice with Non-Alcoholic Fatty Liver Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21239156 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9156

Author(s):

Rachel B. Wilson ◽

Richard Zhang ◽

Yun Jin Chen ◽

Kia M. Peters ◽

Cynthia G. Sawyez ◽

...

Keyword(s):

Weight Loss ◽

Fatty Liver Disease ◽

Restricted Feeding ◽

Liver Inflammation ◽

Obese Mice ◽

Significant Weight Loss ◽

Short Term ◽

Alcoholic Fatty Liver ◽

Ad Libitum ◽

Alcoholic Fatty Liver Disease

Prolonged, isocaloric, time-restricted feeding (TRF) protocols can promote weight loss, improve metabolic dysregulation, and mitigate non-alcoholic fatty liver disease (NAFLD). In addition, 3-day, severe caloric restriction can improve liver metabolism and glucose homeostasis prior to significant weight loss. Thus, we hypothesized that short-term, isocaloric TRF would improve NAFLD and characteristics of metabolic syndrome in diet-induced obese male mice. After 26 weeks of ad libitum access to western diet, mice either continued feeding ad libitum or were provided with access to the same quantity of western diet for 8 h daily, over the course of two weeks. Remarkably, this short-term TRF protocol modestly decreased liver tissue inflammation in the absence of changes in body weight or epidydimal fat mass. There were no changes in hepatic lipid accumulation or other characteristics of NAFLD. We observed no changes in liver lipid metabolism-related gene expression, despite increased plasma free fatty acids and decreased plasma triglycerides in the TRF group. However, liver Grp78 and Txnip expression were decreased with TRF suggesting hepatic endoplasmic reticulum (ER) stress and activation of inflammatory pathways may have been diminished. We conclude that two-week, isocaloric TRF can potentially decrease liver inflammation, without significant weight loss or reductions in hepatic steatosis, in obese mice with NAFLD.

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Short‐term aerobic exercise improves hepatic lipid composition, insulin sensitivity, and circulating HMW adiponectin independent of weight loss in patients with non‐alcoholic fatty liver disease

The FASEB Journal ◽

10.1096/fasebj.25.1_supplement.1103.7 ◽

2011 ◽

Vol 25 (S1) ◽

Author(s):

Jacob M Haus ◽

Thomas P.J. Solomon ◽

Emily S Louis ◽

Karen R Kelly ◽

Aimee J Patrick‐Melin ◽

...

Keyword(s):

Weight Loss ◽

Liver Disease ◽

Insulin Sensitivity ◽

Fatty Liver ◽

Lipid Composition ◽

Fatty Liver Disease ◽

Short Term ◽

Alcoholic Fatty Liver ◽

Hmw Adiponectin ◽

Alcoholic Fatty Liver Disease

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Maresin 1 improves insulin sensitivity and attenuates adipose tissue inflammation in ob/ob and diet‐induced obese mice

The FASEB Journal ◽

10.1096/fj.201600859r ◽

2017 ◽

Vol 31 (5) ◽

pp. 2135-2145 ◽

Cited By ~ 46

Author(s):

Leyre Martínez-Fernández ◽

Pedro González-Muniesa ◽

Laura M. Laiglesia ◽

Neira Sáinz ◽

Pedro L. Prieto-Hontoria ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Adipose Tissue Inflammation ◽

Obese Mice ◽

Tissue Inflammation ◽

Maresin 1

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Impact of short-term exercise training intensity on β-cell function in older obese adults with prediabetes

Journal of Applied Physiology ◽

10.1152/japplphysiol.00680.2018 ◽

2018 ◽

Vol 125 (6) ◽

pp. 1979-1986 ◽

Cited By ~ 4

Author(s):

Steven K. Malin ◽

Monique E. Francois ◽

Natalie Z. M. Eichner ◽

Nicole M. Gilbertson ◽

Emily M. Heiston ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Insulin Sensitivity ◽

Exercise Training ◽

Glucose Tolerance ◽

Cell Function ◽

Β Cell ◽

Short Term ◽

Β Cell Function ◽

High Intensity Interval

The effect of work-matched exercise intensity on β-cell function is unknown in people with prediabetes before clinical weight loss. We determined if short-term moderate continuous (CONT) vs. high-intensity interval (INT) exercise increased β-cell function. Thirty-one subjects (age: 61.4 ± 2.5 yr; body mass index: 32.1 ± 1.0 kg/m2) with prediabetes [American Diabetes Association criteria, 75-g oral glucose tolerance test (OGTT)] were randomized to work-matched CONT (70% HRpeak) or INT (3 min 90% HRpeak and 3 min 50% HRpeak) exercise for 60 min/day over 2 wk. A 75-g 2-h OGTT was conducted after an overnight fast, and plasma glucose, insulin, C-peptide, and free fatty acids were determined for calculations of skeletal muscle [oral minimal model (OMM)], hepatic (homeostatic model of insulin resistance), and adipose (Adipose-IR) insulin sensitivity. β-Cell function was defined from glucose-stimulated insulin secretion (GSIS, deconvolution modeling) and the disposition index (DI). Glucagon-like polypeptide-1 [GLP-1(active)] and glucose-dependent insulinotropic polypeptide (GIP) were also measured during the OGTT, along with peak oxygen consumption and body composition. CONT and INT increased skeletal muscle- but not hepatic- or adipose-derived DI ( P < 0.05). Although both treatments tended to reduce fasting GLP-1(active) ( P = 0.08), early phase GLP-1(active) increased post-CONT and INT training ( P < 0.001). Interestingly, CONT exercise increased fasting GIP compared with decreases in INT ( P = 0.02). Early and total-phase skeletal muscle DI correlated with decreased total glucose area under the curve ( r = −0.52, P = 0.002 and r = −0.50, P = 0.003, respectively). Independent of intensity, short-term training increased pancreatic function adjusted to skeletal muscle in relation to improved glucose tolerance in adults with prediabetes. Exercise also uniquely affected GIP and GLP-1(active). Further work is needed to elucidate the dose-dependent mechanism(s) by which exercise impacts glycemia. NEW & NOTEWORTHY Exercise is cornerstone for reducing blood glucose, but whether high-intensity interval training is better than moderate continuous exercise is unclear in people with prediabetes before weight loss. We show that 2 wk of exercise training, independent of intensity, increased pancreatic function in relation to elevated glucagon-like polypeptide-1 secretion. Furthermore, β-cell function, but not insulin sensitivity, was also correlated with improved glucose tolerance. These data suggest that β-cell function is a strong predictor of glycemia regardless of exercise intensity.

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Short-term low-calorie diet remodels skeletal muscle lipid profile and metabolic gene expression in obese adults

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00253.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. E178-E185 ◽

Cited By ~ 1

Author(s):

Carolina Nylén ◽

Leonidas S. Lundell ◽

Julie Massart ◽

Juleen R. Zierath ◽

Erik Näslund

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Weight Loss ◽

Insulin Sensitivity ◽

Dietary Intervention ◽

Short Term ◽

Obese Adults ◽

Diet Intervention ◽

Metabolic Gene Expression ◽

Calorie Diet

Diet intervention in obese adults is the first strategy to induce weight loss and improve insulin sensitivity. We hypothesized that improvements in insulin sensitivity after weight loss from a short-term dietary intervention tracks with alterations in expression of metabolic genes and abundance of specific lipid species. Eight obese, insulin-resistant, nondiabetic adults were recruited to participate in a 3-wk low-calorie diet intervention cohort study (1,000 kcal/day). Fasting blood samples and vastus lateralis skeletal muscle biopsies were obtained before and after the dietary intervention. Clinical chemistry and measures of insulin sensitivity were determined. Unbiased microarray gene expression and targeted lipidomic analysis of skeletal muscle was performed. Body weight was reduced, insulin sensitivity [measured by homeostatic model assessment of insulin resistance, (HOMA-IR)] was enhanced, and serum insulin concentration and blood lipid (triglyceride, cholesterol, LDL, and HDL) levels were improved after dietary intervention. Gene set enrichment analysis of skeletal muscle revealed that biosynthesis of unsaturated fatty acid was among the most enriched pathways identified after dietary intervention. mRNA expression of PDK4 and MLYCD increased, while SCD1 decreased in skeletal muscle after dietary intervention. Dietary intervention altered the intramuscular lipid profile of skeletal muscle, with changes in content of phosphatidylcholine and triglyceride species among the pronounced. Short-term diet intervention and weight loss in obese adults alters metabolic gene expression and reduces specific phosphatidylcholine and triglyceride species in skeletal muscle, concomitant with improvements in clinical outcomes and enhanced insulin sensitivity.

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