GDF15 promotes weight loss by enhancing energy expenditure in muscle

Nature, Год журнала: 2023, Номер 619(7968), С. 143 - 150

Опубликована: Июнь 28, 2023

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, most individuals, usually not maintained partly due to physiological adaptations suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment rodents fed high-fat diet recombinant growth differentiating factor 15 (GDF15) reduces obesity improves glycaemic control through glial-cell-derived neurotrophic family receptor α-like (GFRAL)-dependent suppression food intake4-7. Here we find that, addition suppressing appetite, GDF15 counteracts compensatory reductions eliciting greater (NAFLD) compared caloric alone. This effect maintain expenditure during calorie requires GFRAL-β-adrenergic-dependent signalling axis increases acid oxidation calcium futile cycling skeletal muscle mice. These data indicate therapeutic targeting GDF15-GFRAL pathway may be useful maintaining restriction.

Язык: Английский

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Mechanisms and possible hepatoprotective effects of glucagon-like peptide-1 receptor agonists and other incretin receptor agonists in non-alcoholic fatty liver disease

˜The œLancet. Gastroenterology & hepatology, Год журнала: 2023, Номер 8(2), С. 179 - 191

Опубликована: Янв. 5, 2023

Язык: Английский

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Changes in lean body mass with glucagon‐like peptide‐1‐based therapies and mitigation strategies

Diabetes Obesity and Metabolism, Год журнала: 2024, Номер 26(S4), С. 16 - 27

Опубликована: Июнь 27, 2024

Abstract Weight loss induced by glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and dual (GLP‐1R)/glucose‐dependent insulinotropic polypeptide is coming closer to the magnitudes achieved with surgery. However, greater weight there concern about potential side effects on muscle quantity (mass), health function. There heterogeneity in reported of GLP‐1‐based therapies lean mass changes clinical trials: some studies, reductions range between 40% 60% as a proportion total lost, while other studies show approximately 15% or less lost. are several reasons underlying this heterogeneity, including population, drug‐specific/molecular, comorbidity effects. Furthermore, may not always reflect former measure includes only but also organs, bone, fluids, water fat tissue. Based contemporary evidence addition magnetic resonance imaging‐based skeletal GLP‐1RA treatments appear be adaptive: volume seem commensurate what expected given ageing, disease status, achieved, improvement insulin sensitivity infiltration likely contributes an adaptive process improved quality, lowering probability for strength Nevertheless, factors such older age severity influence selection appropriate candidates these due risk sarcopenia. To further improve during loss, pharmacological maintain designed combination under development. Future research should focus more accurate meaningful assessments mass, composition, well function, mobility strength, better define their impact substantial number patients who will taking medications into future.

Язык: Английский

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Obesity-induced and weight-loss-induced physiological factors affecting weight regain

Nature Reviews Endocrinology, Год журнала: 2023, Номер 19(11), С. 655 - 670

Опубликована: Сен. 11, 2023

Язык: Английский

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Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition?

Diabetes Care, Год журнала: 2024, Номер 47(10), С. 1718 - 1730

Опубликована: Апрель 30, 2024

This narrative review highlights the degree to which new antiobesity medications based on gut-derived nutrient-stimulated hormones (incretins) cause loss of lean mass, and importance resistance exercise preserve muscle. Glucagon-like peptide 1 receptor agonists (GLP-1RA) induce substantial weight in randomized trials, effects that may be enhanced combination with glucose-dependent insulinotropic polypeptide (GIP) agonists. Liraglutide semaglutide (GLP-1RA), tirzepatide (GLP-1 GIP dual agonist), retatrutide (GLP-1, GIP, glucagon triple agonist) are peptides incretin agonist activity ∼15-24% adults overweight obesity, alongside beneficial impacts blood pressure, cholesterol, glucose, insulin. However, these agents also rapid significant mass (∼10% or ∼6 kg), comparable a decade more aging. Maintaining muscle function as humans age is crucial avoiding sarcopenia frailty, strongly linked morbidity mortality. Studies indicate supervised training interventions duration >10 weeks can elicit large increases (∼3 kg) strength (∼25%) men women. After low-calorie diet, combining aerobic liraglutide improved maintenance compared either alone. Retaining during therapy could blunt body (and fat) regain cessation pharmacotherapy. We propose tailored recommended an adjunct optimize changes composition by preserving while achieving fat loss.

Язык: Английский

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Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism

Molecular Metabolism, Год журнала: 2024, Номер 80, С. 101880 - 101880

Опубликована: Янв. 11, 2024

Glucagon-like peptide 1 (GLP-1) receptor agonists reduce food intake, producing remarkable weight loss in overweight and obese individuals. While much of this is fat mass, there also a lean similar to other approaches that induce calorie deficit. Targeting signaling pathways regulate skeletal muscle hypertrophy promising avenue preserve mass modulate body composition. Myostatin Activin A are TGFβ-like ligands signal via the activin type II receptors (ActRII) antagonize growth. Pre-clinical clinical studies demonstrate ActRII blockade induces reduces mass. In manuscript, we test hypothesis combined plus GLP-1 agonist will leading improvements skeletomuscular metabolic function enhanced loss. study, explore therapeutic potential bimagrumab, monoclonal antibody against ActRII, modify composition alone during induced by semaglutide diet-induced mice. Mechanistically, define specific role anabolic kinase Akt mediating hypertrophic effects inhibition vivo. Treatment mice with bimagrumab ∼10% increase while simultaneously decreasing Daily treatment potently decreased weight; included significant decrease both Combination led superior preserving despite reduced intake. drugs was associated improved outcomes, increased exercise performance. Deletion isoforms modestly reduced, but did not prevent, driven inhbition. Collectively, these data improves parameters deficit agonism existence Akt-independent supporting absence signaling.

Язык: Английский

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Muscle Mass and Glucagon-Like Peptide-1 Receptor Agonists: Adaptive or Maladaptive Response to Weight Loss?

Circulation, Год журнала: 2024, Номер 150(16), С. 1288 - 1298

Опубликована: Окт. 14, 2024

Recent studies have shown that pharmacologic weight loss with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and combination therapies is approaching magnitudes achieved surgery. However, as more achieved, there concern for potential adverse effects on muscle quantity, composition, function. This primer aims to address whether muscle-related changes associated treatments such GLP-1 RAs may be maladaptive (ie, adversely affecting health or function), adaptive a physiologic response maintaining minimally perhaps an enhanced improved function after treatment). Based contemporary evidence the addition of using magnetic resonance imaging, skeletal RA appear adaptive: in volume z-score indicate change commensurate what expected given aging, disease status, improvement insulin sensitivity fat infiltration likely contributes process quality, lowering probability strength Nevertheless, factors older age prefrailty influence selection appropriate candidates these because risk sarcopenia. Several maintain improve mass designed GLP-1–based are under development. For future development (and other therapies) loss, well patient-centered treatment optimization, introduction objective comprehensive ways assessing (including accurate meaningful assessments function, mobility, strength) important substantial numbers patients who will taking medications into future.

Язык: Английский

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Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation

Cell Metabolism, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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A cellular and molecular basis of leptin resistance

Cell Metabolism, Год журнала: 2025, Номер 37(3), С. 723 - 741.e6

Опубликована: Март 1, 2025

Similar to most humans with obesity, diet-induced obese (DIO) mice have high leptin levels and fail respond the exogenous hormone, suggesting that their obesity is caused by resistance, pathogenesis of which unknown. We found treatment reduced plasma leucine methionine, mTOR-activating ligands, leading us hypothesize chronic mTOR activation might reduce signaling. Rapamycin, an inhibitor, fat mass increased sensitivity in DIO but not defects Rapamycin restored leptin's actions on POMC neurons failed weight melanocortin whereas POMC-specific mutations activators decreased gain mice. Thus, activity necessary sufficient for development resistance mice, establishing a key pathogenic mechanism obesity.

Язык: Английский

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Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss

Obesity, Год журнала: 2022, Номер 30(4), С. 841 - 857

Опубликована: Март 25, 2022

Abstract New appetite‐regulating antiobesity treatments such as semaglutide and agents under investigation tirzepatide show promise in achieving weight loss of 15% or more. Energy expenditure, fat oxidation, lean mass preservation are important determinants weight‐loss maintenance beyond appetite regulation. This review discusses prior failures clinical development drugs targeting energy expenditure explores novel strategies for expenditure: mitochondrial proton leak, uncoupling, dynamics, biogenesis; futile calcium substrate cycling; leptin maintenance; increased sympathetic nervous system activity; browning white fat. Relevant targets preserving also reviewed: growth hormone, activin type II receptor inhibition, urocortin 2 3. We endorse moderate modulation combination with efficient reduction a means obtaining significant, safe, long‐lasting loss. Furthermore, we suggest that the regulatory guidelines should be revisited to focus more on quality its rather than absolute Commitment this research both from scientific point view could signal beginning next era obesity therapies.

Язык: Английский

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