Anti-obesity drug discovery: advances and challenges

Müller, Timo D.; Blüher, Matthias; Tschöp, Matthias H.; DiMarchi, Richard D.

doi:10.1038/s41573-021-00337-8

Cited by 516 publications

(507 citation statements)

References 329 publications

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“…Thus far, these dual and triagonist peptide agents show superior benefits to promote weight loss and glycemic control in clinical studies compared to single peptide-based therapies and thus may be able to promote β-cell health as well as relieve the peripheral insulin demand [ 210 , 211 , 212 , 213 ]; however, the long-term impact of these polyagonist peptides on β-cell function is not yet known. The observation that weight loss alone can lead to a marked improvement in β-cell function has spurred continued interest in anti-obesity therapies as a key goal in developing more effective T2D therapies [ 214 , 215 ]. Collectively, these observations suggest that relieving the demand for insulin release via independent mechanisms can promote β-cell health and improve long-term outcomes [ 12 , 17 ], whereas β-cell exhaustion from persistently elevated insulin secretion may be an underlying cause of dysregulated secretion in T2D and contribute to the final transition to β-cell failure [ 17 , 29 , 216 ].…”

Section: T2d Therapies: What Can We Learn About β-Cell Plasticity?mentioning

confidence: 99%

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

et al. 2022

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Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). Nutrient-stimulated increases in proinsulin biosynthesis may initiate this β-cell adaptive compensation; however, the molecular regulators of secretory expansion that accommodate the increased biosynthetic burden of packaging and producing additional insulin granules, such as enhanced ER and Golgi functions, remain poorly defined. As these adaptive mechanisms fail and T2D progresses, the β-cell succumbs to metabolic defects resulting in alterations to glucose metabolism and a decline in nutrient-regulated secretory functions, including impaired proinsulin processing and a deficit in mature insulin-containing secretory granules. In this review, we will discuss how the adaptative plasticity of the pancreatic islet β-cell’s secretory program allows insulin production to be carefully matched with nutrient availability and peripheral cues for insulin signaling. Furthermore, we will highlight potential defects in the secretory pathway that limit or delay insulin granule biosynthesis, which may contribute to the decline in β-cell function during the pathogenesis of T2D.

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Section: T2d Therapies: What Can We Learn About β-Cell Plasticity?mentioning

confidence: 99%

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

et al. 2022

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“…For each molecule, we start by inspecting its functions in adipogenesis-related molecular and cellular mechanism, then extend this to in vivo validation in mice, though only a few compounds entered clinical trials. The gap between animal and human studies also represents one of the major challenges for anti-obesity drug discovery [11].…”

Section: Mechanism Of Adipogenesismentioning

confidence: 99%

“…However, there is still an unmet need for effective anti-obesity therapeutics. Most currently available drugs still function by restricting energy intake, such as GLP1R agonists [11]. Here we reviewed multiple compounds regulating signaling or epigenetic status in adipogenesis.…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

The Potential to Fight Obesity with Adipogenesis Modulating Compounds

Zhao

Zhou

2022

IJMS

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Obesity is an increasingly severe public health problem, which brings huge social and economic burdens. Increased body adiposity in obesity is not only tightly associated with type 2 diabetes, but also significantly increases the risks of other chronic diseases including cardiovascular diseases, fatty liver diseases and cancers. Adipogenesis describes the process of the differentiation and maturation of adipocytes, which accumulate in distributed adipose tissue at various sites in the body. The major functions of white adipocytes are to store energy as fat during periods when energy intake exceeds expenditure and to mobilize this stored fuel when energy expenditure exceeds intake. Brown/beige adipocytes contribute to non-shivering thermogenesis upon cold exposure and adrenergic stimulation, and thereby promote energy consumption. The imbalance of energy intake and expenditure causes obesity. Recent interest in epigenetics and signaling pathways has utilized small molecule tools aimed at modifying obesity-specific gene expression. In this review, we discuss compounds with adipogenesis-related signaling pathways and epigenetic modulating properties that have been identified as potential therapeutic agents which cast some light on the future treatment of obesity.

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“…However, when lifestyle modification fails, before resorting to bariatric surgery, pharmacological intervention should be considered as an important alternative or adjunct therapy for weight loss. In this sense, achieving weight normalization by undergoing long-term drug therapy with sufficient tolerability and safety remained an unattainable challenge until recently [ 2 ].…”

mentioning

confidence: 99%

“…The endocannabinoid receptor CB 1 R in the brain is involved in the regulation of food intake and energy homeostasis. Selective antagonism or inverse agonism of this receptor in the brain using drugs such as rimonabant reduced appetite, enhanced thermogenesis and diminished lipogenesis in several human trials, but important psychiatric side-effects precluded its approval for the treatment of obesity by the FDA and forced its withdrawal from the European markets [ 2 ]. However, the peripheral antagonism of this receptor with drugs that do not cross the blood–brain barrier has been proposed as an interesting strategy for the management of many obesity-associated metabolic alterations [ 4 ].…”

mentioning

confidence: 99%