Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure

Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism genes were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.

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Journal of Clinical and Translational Science ◽

10.1017/cts.2017.54 ◽

2017 ◽

Vol 1 (S1) ◽

pp. 11-11

Author(s):

David M. Presby ◽

Rebecca M. Foright ◽

Julie A. Houck ◽

Ginger C. Johnson ◽

L. Allyson Checkley ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Energy Expenditure ◽

Metabolic Rate ◽

Total Energy ◽

Weight Regain ◽

Resting Metabolic Rate ◽

Weight Loss Maintenance ◽

Oxidative Capacity ◽

Total Energy Expenditure

OBJECTIVES/SPECIFIC AIMS: Obesity is a rapidly growing epidemic and long-term interventions aimed to reduce body weight are largely unsuccessful due to an increased drive to eat and a reduced metabolic rate established during weight loss. Previously, our lab demonstrated that exercise has beneficial effects on weight loss maintenance by increasing total energy expenditure above and beyond the cost of an exercise bout and reducing the drive to eat when allowed to eat ad libitum (relapse). We hypothesized that exercise’s ability to counter these obesogenic-impetuses are mediated via improvements in skeletal muscle oxidative capacity, and tested this using a mouse model with augmented oxidative capacity in skeletal muscle. METHODS/STUDY POPULATION: We recapitulated the exercise-induced improvements in oxidative capacity using FVB mice that overexpress lipoprotein lipase in skeletal muscle (mLPL). mLPL and wild type (WT) mice were put through a weight-loss-weight-regain paradigm consisting of a high fat diet challenge for 13 weeks, with a subsequent 1-week calorie-restricted medium fat diet to induce a ~15% weight loss. This newly established weight was maintained for 2 weeks and followed with a 24-hour relapse. Metabolic phenotype was characterized by indirect calorimetry during each phase. At the conclusion of the relapse day, mice were sacrificed and tissues were harvested for molecular analysis. RESULTS/ANTICIPATED RESULTS: During weight loss maintenance, mLPL mice had a higher metabolic rate (p=0.0256) that was predominantly evident in the dark cycle (p=0.0015). Furthermore, this increased metabolic rate was not due to differences in activity (p=0.2877) or resting metabolic rate (p=0.4881). During relapse, mLPL mice ingested less calories and were protected from rapid weight regain (p=0.0235), despite WT mice exhibiting higher metabolic rates during the light cycle (p=0.0421). DISCUSSION/SIGNIFICANCE OF IMPACT: These results highlight the importance of muscular oxidative capacity in preventing a depression in total energy expenditure during weight loss maintenance, and in curbing overfeeding and weight regain during a relapse. Moreover, our data suggest that the thermic effect of food is responsible for the differences in metabolic rate, because no differences were found in activity or resting metabolic rate. Additional studies are warranted to determine the molecular mechanisms driving the ability of oxidative capacity to assist with weight loss maintenance.

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Dynamic changes of muscle insulin sensitivity after metabolic surgery

Nature Communications ◽

10.1038/s41467-019-12081-0 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 12

Author(s):

Sofiya Gancheva ◽

Meriem Ouni ◽

Tomas Jelenik ◽

Chrysi Koliaki ◽

Julia Szendroedi ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Metabolic Surgery ◽

Muscle Metabolism ◽

Respiratory Control ◽

Oxidative Capacity ◽

Initial Weight Loss ◽

Expression Of Genes

Abstract The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear. We monitored skeletal muscle metabolism in obese individuals before and over 52 weeks after metabolic surgery. Initial weight loss occurs in parallel with a decrease in muscle oxidative capacity and respiratory control ratio. Persistent elevation of intramyocellular lipid intermediates, likely resulting from unrestrained adipose tissue lipolysis, accompanies the lack of rapid changes in insulin sensitivity. Simultaneously, alterations in skeletal muscle expression of genes involved in calcium/lipid metabolism and mitochondrial function associate with subsequent distinct DNA methylation patterns at 52 weeks after surgery. Thus, initial unfavorable metabolic changes including insulin resistance of adipose tissue and skeletal muscle precede epigenetic modifications of genes involved in muscle energy metabolism and the long-term improvement of insulin sensitivity.

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Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure

Diabetes ◽

10.2337/db20-0763 ◽

2021 ◽

pp. db200763

Author(s):

David M Presby ◽

Michael C Rudolph ◽

Vanessa D Sherk ◽

Matthew R Jackman ◽

Rebecca M Foright ◽

...

Keyword(s):

Skeletal Muscle ◽

Energy Expenditure ◽

Lipoprotein Lipase ◽

Weight Regain

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β-Adrenergically Stimulated Fat Oxidation Is Diminished in Middle-Aged Compared to Young Subjects*

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.84.10.6043 ◽

1999 ◽

Vol 84 (10) ◽

pp. 3764-3769

Author(s):

E. E. Blaak ◽

M. A. van Baak ◽

W. H. M. Saris

Keyword(s):

Skeletal Muscle ◽

Energy Expenditure ◽

Total Energy ◽

Fat Oxidation ◽

Substrate Utilization ◽

Total Energy Expenditure ◽

Adrenergic Stimulation ◽

Middle Aged ◽

Older Subjects ◽

Young Subjects

Abstract The effect of aging on β-adrenergically mediated substrate utilization was investigated in nine young (25.2 ± 1.7 yr old) and eight older males (52.9 ± 2.1 yr old), matched for body weight and body composition. In a first experiment, the nonselectiveβ -agonist isoprenaline (ISO) was infused in increasing standardized doses, and during each infusion period energy expenditure and substrate utilization were determined by indirect calorimetry. In a second experiment, forearm skeletal muscle metabolism was studied during a standardized infusion dose of ISO (19 ng/kg fat-free mass·min). During β-adrenergic stimulation there was an increased carbohydrate oxidation (at an ISO infusion dose of 24 ng/kg fat-free mass·min, 31% vs. 21% of total energy expenditure; P < 0.05) and a decreased fat oxidation (51 vs. 62 of total energy expenditure; P < 0.05) in older compared to young subjects. Skeletal muscle lactate release significantly increased in the older subjects (from −175 ± 32 to −366 ± 66 nmol/100 mL forearm tissue·min), whereas there was no change in young subjects (from− 32 ± 21 to 23 ± 57 nmol/100 mL forearm tissue·min; interaction group × ISO, P < 0.01). Additionally, there was a tendency toward a blunted ISO-induced increase in nonesterified fatty acid uptake in the older subjects (interaction group × ISO, P = 0.062). Thus, middle-aged subjects have a blunted ability to oxidize fat during β-adrenergic stimulation compared to young subjects. This diminished fat oxidation may be an important etiological factor in the age-related increase in body fatness and obesity by favoring fat storage above oxidation.

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1-Sarcosine-angiotensin II infusion effects on food intake, weight loss, energy expenditure, and skeletal muscle UCP3 gene expression in a rat model

Journal of Cachexia Sarcopenia and Muscle ◽

10.1007/s13539-014-0133-2 ◽

2014 ◽

Vol 5 (3) ◽

pp. 239-246 ◽

Cited By ~ 10

Author(s):

S. A. Cichello ◽

R. S. Weisinger ◽

J. Schuijers ◽

M. Jois

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Weight Loss ◽

Angiotensin Ii ◽

Food Intake ◽

Energy Expenditure ◽

Rat Model ◽

Ucp3 Gene

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Regular exercise potentiates energetically expensive hepatic de novo lipogenesis during early weight regain

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00074.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. R684-R695

Author(s):

David M. Presby ◽

L. Allyson Checkley ◽

Matthew R. Jackman ◽

Janine A. Higgins ◽

Kenneth L. Jones ◽

...

Keyword(s):

Weight Loss ◽

Energy Expenditure ◽

De Novo ◽

Energy Gap ◽

Cholesterol Biosynthesis ◽

Density Lipoprotein ◽

De Novo Lipogenesis ◽

Positive Energy ◽

Hepatic Expression ◽

Expression Of Genes

Exercise is a potent facilitator of long-term weight loss maintenance (WLM), whereby it decreases appetite and increases energy expenditure beyond the cost of the exercise bout. We have previously shown that exercise may amplify energy expenditure through energetically expensive nutrient deposition. Therefore, we investigated the effect of exercise on hepatic de novo lipogenesis (DNL) during WLM and relapse to obesity. Obese rats were calorically restricted with (EX) or without (SED) treadmill exercise (1 h/day, 6 days/wk, 15 m/min) to induce and maintain weight loss. After 6 wk of WLM, subsets of WLM-SED and WLM-EX rats were allowed ad libitum access to food for 1 day to promote relapse (REL). An energy gap-matched group of sedentary, relapsing rats (REL-GM) were provided a diet matched to the positive energy imbalance of the REL-EX rats. During relapse, exercise increased enrichment of hepatic DN-derived lipids and induced hepatic molecular adaptations favoring DNL compared with the gap-matched controls. In the liver, compared with both REL-SED and REL-GM rats, REL-EX rats had lower hepatic expression of genes required for cholesterol biosynthesis; greater hepatic expression of genes that mediate very low-density lipoprotein synthesis and secretion; and greater mRNA expression of Cyp27a1, which encodes an enzyme involved in the biosynthesis of bile acids. Altogether, these data provide compelling evidence that the liver has an active role in exercise-mediated potentiation of energy expenditure during early relapse.

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The Effects of Caffeine and Green Tea on Energy Expenditure, Fat Oxidation, Weight Loss, and Weight Maintenance

Weight Control and Slimming Ingredients in Food Technology ◽

10.1002/9780813819679.ch10 ◽

2009 ◽

pp. 159-176

Author(s):

Rick Hursel ◽

Margriet Westerterp-Plantenga

Keyword(s):

Weight Loss ◽

Energy Expenditure ◽

Green Tea ◽

Weight Maintenance ◽

Fat Oxidation

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Changes in Energy Expenditure and Substrate Oxidation Resulting from Weight Loss in Obese Men and Women: Is There an Important Contribution of Leptin?1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.85.4.6500 ◽

2000 ◽

Vol 85 (4) ◽

pp. 1550-1556 ◽

Cited By ~ 2

Author(s):

Eric Doucet ◽

Sylvie St. Pierre ◽

Natalie Alméras ◽

Pascale Mauriège ◽

Denis Richard ◽

...

Keyword(s):

Weight Loss ◽

Energy Expenditure ◽

Resting Energy Expenditure ◽

Fat Oxidation ◽

Substrate Oxidation ◽

Energy Restriction ◽

Fat Free Mass ◽

Hormonal Changes ◽

Men And Women ◽

The Impact

The aim of the present study was to determine the impact of weight loss and its related metabolic and hormonal changes on resting energy expenditure (REE) and substrate oxidation. Forty subjects (16 men and 24 women) took part in a 15-week weight loss program that consisted of drug therapy (fenfluramine, 60 mg/day) or placebo coupled to an energy restriction (−700 Cal/day). Subjects were asked to come to the laboratory after an overnight fast for an indirect calorimetry measurement before and after weight loss. Fasting blood samples were also drawn and were analyzed for plasma glucose, insulin, leptin, and free fatty acid determinations. This program reduced body weight by 11% and 9% (P < 0.01) in men and women, respectively. Fat mass (FM) and fat-free mass (FFM) were also significantly reduced in both sexes. A significant decrease in REE (13%; P < 0.01) and fat oxidation (11%; P = 0.08) was observed in men in response to this program, whereas no significant differences were noted for these variables in women. In men, positive correlations were found between changes in FFM and energy-related variables, whereas the best predictor of changes in REE and substrate oxidation was the change in FM in women. The most important finding of this study is that in men, the association between changes in fasting plasma leptin and changes in REE (r = 0.50; P < 0.01) and fat oxidation (r = 0.63; P < 0.01) persist after correction for changes in body composition. These results suggest that a comparable weight loss is accompanied by a greater decrease in REE and substrate oxidation in men than in women, and that these changes are better explained by changes in leptinemia in men and by changes in FM in women.

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