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In 1902, Ralph Larrabee provided intriguing evidence suggesting parallels between the changes in white blood cell counts observed in Boston Marathon runners and those seen in specific disease states. Notably he also noted a considerable leukocytosis of the inflammatory type, suggesting a potential link between extreme exercise and inflammatory responses. This early observation laid the groundwork for further investigations into the complex relationship between exercise intensity, immune system activation, and health outcomes, igniting an ongoing debate about the impact of exercise on the immune system.

Today we know exercise shows quantifiable and observable benefits to human health across multiple scales, but the specific genetic and biological processes and pathways underlying these benefits remain unclear. This is primarily caused by individuals exhibiting significant physiological variations in their response to exercise training, coupled with the diverse methods, subjects and timelines used in studying this phenomenon, which impacts the potential for clear and reproducible analysis. A deeper grasp of the metabolic and cellular impacts of exercise could lead to more targeted exercise approaches. Additionally, unraveling the molecular shifts induced by various exercise methods may hasten the identification of pharmaceutical targets for improving metabolic well-being. To combat the global pandemic of physical inactivity and its associated toll of 5.3 million deaths annually, we must gain a better understanding of the fundamental principles governing physical activity’s benefits.

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Lead-in calorie restriction enhances the weight-lowering efficacy of incretin hormone-based pharmacotherapies in mice

Jonas Petersen, Christoffer Merrild, Jens Lund, Stephanie Holm, Christoffer Clemmensen

Lead-in calorie restriction enhances the weight-lowering efficacy of incretin hormone-based pharmacotherapies in mice

 

Objectives

The potential benefits of combining lifestyle changes with weight loss pharmacotherapies for obesity treatment are underexplored. Building on recent clinical observations, this study aimed to determine whether “lead-in” calorie restriction before administering clinically approved weight loss medications enhances the maximum achievable weight loss in preclinical models.

Methods

Diet-induced obese mice (DIO) were exposed to 7 or 14 days of calorie restriction before initiating treatment with semaglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), tirzepatide (a GLP-1R/glucose insulinotropic peptide receptor (GIPR) co-agonist), or setmelanotide (a melanocortin-4 receptor (MC4R) agonist). Follow-up assessments using indirect calorimetry determined the contributions of energy intake and expenditure linked to consecutive exposure to dieting followed by pharmacotherapy.

Results

Calorie restriction prior to treatment with semaglutide or tirzepatide enhanced the weight loss magnitude of both incretin-based therapies in DIO mice, reflected by a reduction in fat mass and linked to reduced energy intake and a less pronounced adaptive drop in energy expenditure. These benefits were not observed with the MC4R agonist, setmelanotide.

Conclusions

Our findings provide compelling evidence that calorie restriction prior to incretin-based therapy enhances the achievable extent of weight loss, as reflected in a weight loss plateau at a lower level compared to that of treatment without prior calorie reduction. This work suggests that more intensive lifestyle interventions should be considered prior to pharmacological treatment, encouraging further exploration and discussion of the current standard of care.

 

 

Articles in Press

Lead-in calorie restriction enhances the weight-lowering efficacy of incretin hormone-based pharmacotherapies in mice

Jonas Petersen, Christoffer Merrild, Jens Lund, Stephanie Holm, Christoffer Clemmensen

Lead-in calorie restriction enhances the weight-lowering efficacy of incretin hormone-based pharmacotherapies in mice

 

Objectives

The potential benefits of combining lifestyle changes with weight loss pharmacotherapies for obesity treatment are underexplored. Building on recent clinical observations, this study aimed to determine whether “lead-in” calorie restriction before administering clinically approved weight loss medications enhances the maximum achievable weight loss in preclinical models.

Methods

Diet-induced obese mice (DIO) were exposed to 7 or 14 days of calorie restriction before initiating treatment with semaglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), tirzepatide (a GLP-1R/glucose insulinotropic peptide receptor (GIPR) co-agonist), or setmelanotide (a melanocortin-4 receptor (MC4R) agonist). Follow-up assessments using indirect calorimetry determined the contributions of energy intake and expenditure linked to consecutive exposure to dieting followed by pharmacotherapy.

Results

Calorie restriction prior to treatment with semaglutide or tirzepatide enhanced the weight loss magnitude of both incretin-based therapies in DIO mice, reflected by a reduction in fat mass and linked to reduced energy intake and a less pronounced adaptive drop in energy expenditure. These benefits were not observed with the MC4R agonist, setmelanotide.

Conclusions

Our findings provide compelling evidence that calorie restriction prior to incretin-based therapy enhances the achievable extent of weight loss, as reflected in a weight loss plateau at a lower level compared to that of treatment without prior calorie reduction. This work suggests that more intensive lifestyle interventions should be considered prior to pharmacological treatment, encouraging further exploration and discussion of the current standard of care.

 

 

You are what you eat

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