Targeting Energy Expenditure—Drugs for Obesity Treatment

Jimenez-Munoz, Carlos M.; López, M. Allué; Alberício, Fernando; Makowski, Kamil

doi:10.3390/ph14050435

Cited by 20 publications

(18 citation statements)

References 108 publications

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“…Brown adipose tissue (BAT), which contains thermogenic brown and beige adipocytes [ 12 ], is capable of energy dissipation through the production of heat [ 13 ], mainly mediated by Uncoupling protein (UCP) 1-dependent proton leak, which uncouples oxidative phosphorylation from ATP generation in the mitochondria [ 14 ]. BAT plays a key role in maintaining the constant core body temperature through nonshivering thermogenesis [ 15 ] and might open up promising therapeutic opportunities to combat obesity [ 16 ]. BAT can be found in six anatomical regions (cervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominal) in adult humans, which amount to 4.3% of total fat and 1.5% of total body mass [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Mitophagy Mediates the Beige to White Transition of Human Primary Subcutaneous Adipocytes Ex Vivo

et al. 2022

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Brown and beige adipocytes have multilocular lipid droplets, express uncoupling protein (UCP) 1, and promote energy expenditure. In rodents, when the stimulus of browning subsides, parkin-dependent mitophagy is activated and dormant beige adipocytes persist. In humans, however, the molecular events during the beige to white transition have not been studied in detail. In this study, human primary subcutaneous abdominal preadipocytes were differentiated to beige for 14 days, then either the beige culture conditions were applied for an additional 14 days or it was replaced by a white medium. Control white adipocytes were differentiated by their specific cocktail for 28 days. Peroxisome proliferator-activated receptor γ-driven beige differentiation resulted in increased mitochondrial biogenesis, UCP1 expression, fragmentation, and respiration as compared to white. Morphology, UCP1 content, mitochondrial fragmentation, and basal respiration of the adipocytes that underwent transition, along with the induction of mitophagy, were similar to control white adipocytes. However, white converted beige adipocytes had a stronger responsiveness to dibutyril-cAMP, which mimics adrenergic stimulus, than the control white ones. Gene expression patterns showed that the removal of mitochondria in transitioning adipocytes may involve both parkin-dependent and -independent pathways. Preventing the entry of beige adipocytes into white transition can be a feasible way to maintain elevated thermogenesis and energy expenditure.

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Section: Introductionmentioning

confidence: 99%

Mitophagy Mediates the Beige to White Transition of Human Primary Subcutaneous Adipocytes Ex Vivo

et al. 2022

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“…49,107 PL-8905 is in clinical trials after exhibiting minimal side effects, such as changes in blood pressure, in preclinical studies. 49,108 Setmelanotide showed considerable promise with no observed side effects in phase III clinical trials 36 and has now been approved by the FDA. 108 Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), also causes weight loss by reducing appetite.…”

Section: Nonpeptide Ligandsmentioning

confidence: 99%

Melanocortin‐4 receptor complexity in energy homeostasis,obesity and drug development strategies

Fatima

Ahmed

Fakhro

et al. 2022

Diabetes Obesity Metabolism

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The melanocortin‐4 receptor (MC4R) has been critically investigated for the past two decades, and novel findings regarding MC4R signalling and its potential exploitation in weight loss therapy have lately been emphasized. An association between MC4R and obesity is well established, with disease‐causing mutations affecting 1% to 6% of obese patients. More than 200 MC4R variants have been reported, although conflicting results as to their effects have been found in different cohorts. Most notably, some MC4R gain‐of‐function variants seem to rescue obesity and related complications via specific pathways such as beta‐arrestin (ß‐arrestin) recruitment. Broadly speaking, however, dysfunctional MC4R dysregulates satiety and induces hyperphagia. The picture at the mechanistic level is complicated as, in addition to the canonical G stimulatory pathway, the ß‐arrestin signalling pathway and ions (particularly calcium) seem to interact with MC4R signalling to contribute to or alleviate obesity pathogenesis. Thus, the overall complexity of the MC4R signalling spectra has broadened considerably, indicating there is great potential for the development of new drugs to manage obesity and its related complications. Alpha‐melanocyte‐stimulating hormone is the major endogenous MC4R agonist, but structure‐based ligand discovery studies have identified possible superior and selective agonists that can improve MC4R function. However, some of these agonists characterized in vitro and in vivo confer adverse effects in patients, as demonstrated in clinical trials. In this review, we provide a comprehensive insight into the genetics, function and regulation of MC4R and its contribution to obesity. We also outline new approaches in drug development and emerging drug candidates to treat obesity.

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“…Brown adipose tissue (BAT), which contains thermogenic brown and beige adipocytes, is capable for energy dissipation through the production of heat, mainly mediated by Uncoupling protein (UCP) 1-dependent proton leak that uncouples oxidative phosphorylation from ATP generation in the mitochondria [12][13][14].BAT plays a key role in maintaining the constant core body temperature through non-shivering thermogenesis and might open up promising therapeutic opportunities to combat obesity [15,16]. BAT can be found in six anatomical regions (cervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominal) in adult humans, which amounted to 4.3% of total fat and 1.5% of total body mass [17].…”

Section: Introductionmentioning

confidence: 99%

Mitophagy mediates beige to white transition of human primary subcutaneous adipocytes ex vivo

Vámos

Shaw

Varga

et al. 2022

Preprint

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Brown and beige adipocytes have multilocular lipid droplets, express uncoupling protein (UCP) 1, and promote energy expenditure. In rodents, when the stimulus of browning subsides, parkin-dependent mitophagy is activated and dormant beige adipocytes persist. In humans, however, the molecular events during beige to white transition were not studied in detail. In this study, human primary subcutaneous abdominal preadipocytes were differentiated to beige for 14 days, then either the beige culture conditions were applied for additional 14 days or it was replaced by a white medium. Control white adipocytes were differentiated by their specific cocktail for 28 days. Peroxisome proliferator-activated receptor γ-driven beige differentiation resulted in increased mitochondrial biogenesis, UCP1 expression, fragmentation, and respiration as compared to white. Morphology, UCP1-content, mitochondrial fragmentation, and basal respiration of the adipocytes that underwent transition, along with the induction of mitophagy, were similar to control white adipocytes. However, white converted beige adipocytes had a stronger responsiveness to dibutyril-cAMP, which mimics adrenergic stimulus, than the control white ones. Gene expression patterns showed that removal of mitochondria in transitioning adipocytes may involve both parkin-dependent and independent pathways. Preventing entry of beige adipocytes into white transition can be a feasible way to maintain elevated thermogenesis and energy expenditure.

show abstract

Targeting Energy Expenditure—Drugs for Obesity Treatment

Cited by 20 publications

References 108 publications

Mitophagy Mediates the Beige to White Transition of Human Primary Subcutaneous Adipocytes Ex Vivo

Mitophagy Mediates the Beige to White Transition of Human Primary Subcutaneous Adipocytes Ex Vivo

Melanocortin‐4 receptor complexity in energy homeostasis,obesity and drug development strategies

Mitophagy mediates beige to white transition of human primary subcutaneous adipocytes ex vivo

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