Accurately measuring mouse metabolism is crucial for understanding the effects of pharmacological treatments on energy metabolism . Modern metabolic phenotyping systems have allowed for facile and cost-effective analyses of weight gain mechanisms, which is required for effective anti-obesity pharmacotherapy development [17, 18].
Although the weight loss effects of pharmacotherapy generally translate well from rodents to humans, maximal efficacy is usually two to four times lower in humans than it is in rodents, possibly due to higher mass-specific energy expenditure in rodents than humans and a greater contribution of brown adipose tissue (BAT) to metabolic rate . Furthermore, many anti-obesity therapies fail in clinical trials because rodents are resistant to adverse cardiovascular and pulmonary drug effects, and preclinical models often also fail to account for the heterogeneity of patients with obesity . Despite the numerous challenges in the field, several treatments remain promising, including incretin-based therapies, mitochondrial uncouplers, growth differentiation factor 15 (GDF15), and peptide tyrosine tyrosine (PYY), as well as many different types of phytochemicals.
The emergence of peptide analogues in incretin-based therapies has lessened the frequency of adverse gastrointestinal side effects and has enabled more sustained and effective anti-obesity treatment . A 2019 study reported that peptide-based glucose-dependent insulinotropic polypeptide (GIP) receptor agonists optimized for selectivity, cross-species activity, and action duration could consistently lower body weight in DIO mice . Since mammalian organisms govern energy balance through more than one hormone, a major breakthrough in anti-obesity research has been the discovery of poly-agonists that simultaneously target GLP1, GIP, and/or glucagon receptors . Unimolecular GLP1/GIP co-agonism in particular has been shown to correct obesity and glucose tolerance in both obese rodents and NHPs . Tri-agonism, first reported in 2015, has also achieved superior body weight and plasma cholesterol reductions in DIO mice, and some have recently advanced to clinical trials .
Mitochondrial uncouplers work by decreasing mitochondrial coupler efficiency, which can have beneficial health effects. However, mitochondrial uncouplers are generally cytotoxic at high concentrations due to reduced ATP concentration as well as plasma and lysosomal membrane depolarization and permeabilization . The uncoupler 2,4-dinitrophenol (DNP) initially yielded promising anti-obesity results, but was withdrawn from the market and banned from therapeutic use due to multiple adverse effects, including death in some cases. At non-toxic doses, mitochondrial uncouplers can protect cells against death, and so they are still attractive targets for anti-obesity medications. An oral controlled-release DNP formulation recently achieved low-level hepatic mitochondrial uncoupling in rats that reversed hypertriglyceridemia, insulin resistance, hepatic steatosis, and diabetes, while not being associated with any systemic toxicity .
N5,N6-Bis(2-fluorophenyl)[2,1,3]oxadiazolo[4,5-b]pyrazine-5,6-diamine (BAM15) is a novel mitochondria-specific protonophore uncoupler that possesses similar potency to DNP in increasing energy expenditure, but without serious adverse effects. Recently, BAM15 has been demonstrated to reverse DIO and insulin resistance in mice; oral administration of BAM15 can increase nutrient oxidation and reduce body fat mass without altering food intake, lean body mass, or body temperature . Another study demonstrated that BAM15 could stimulate energy expenditure as well as glucose and lipid metabolism to protect against DIO . BAM15-treated mice in this study were resistant to weight gain and exhibited improved body composition compared to control mice as well as glycemic control independent of weight loss.
GDF15 and PPY-Based Therapies
GDF15 is physiologically expressed at low concentrations in multiple tissues, but its levels increase where there is tissue injury, cancer, metabolic disease, CVD, or inflammation . A recent study proposed GDF15 as a potential pharmacotherapy for obesity treatment; recombinant GDF15 was shown to induce weight loss in DIO mice and NHP . However, its sustained efficacy has not yet been demonstrated and safety risks have not been assessed. The major active form of PPY is a high-affinity agonist for the neuropeptide Y receptor type 2; in 2021, it was shown in both rodents and humans that this active form decreases food intake and body weight . Long-acting PPY analogues for obesity treatment are therefore in development, with some already in clinical trials.
Research into phytochemicals for pharmacological obesity management has also gained interest in recent years as several plant-derived chemical constituents have demonstrated significant anti-adipogenic and anti-obesogenic effects . Many polyphenols, for example, have been shown to prevent obesity development through several mechanisms, including increased lipolysis and fatty acid β-oxidation, decreased lipogenesis, adipose tissue and insulin sensitivity modulation, inflammatory response and oxidative stress reduction, and energy expenditure stimulation .
Polyphenols like glabridin, ferulic acid, resveratrol, and quercetin have demonstrated anti-obesity effects in mouse models. A glabridin analogue has recently demonstrated dose-dependent effects on adiposity and fatty liver in HFD-fed obese mice, primarily through increased energy expenditure . Administration of a phenolic-rich extract containing ferulic acid and anthocyanins in HFD-fed obese mice also led to reduced adipose fat mass and adipocyte size, as well as decreased glucose, insulin, and triglyceride levels . Resveratrol has recently been shown to mitigate body weight gain without influencing daily energy intake in HFD-fed obese mice while improving glucose tolerance and insulin sensitivity . Quercetin, one of the most abundant flavonoids found in human dietary sources, has been reported to significantly reduce adipocyte size, attenuate adipose inflammation, and prevent systemic insulin resistance in HFD-fed rats .
The alkaloid capsiate, a capsaicin analog, has been shown to enhance energy expenditure comparably to capsaicin without unpleasant side effects like gastritis; in one study, capsiate intake in HFD-fed mice combined with exercise training reduced the abdominal fat rate compared to exercise training alone . Alkaloid combination with polyphenols has also exhibited anti-obesity effects in mice; chlorogenic acid and caffeine administration in HFD-fed obese mice effectively decreased body weight gain and intraperitoneal adipose tissue weight .
The carotenoid lycopene has been shown to exhibit anti-oxidative, anti-inflammatory, and neuroprotective effects . In DIO mice, lycopene was able to suppress body weight gain, block lipid accumulation in adipose tissue, and improve insulin resistance in white adipose tissue (WAT) . Lycopene has also been shown to attenuate inflammation and insulin resistance in the epididymal WAT and liver of HFD-fed obese mice by facilitating adipose tissue macrophage polarization . Another carotenoid, β-cryptoxanthin, reduced body fat gain and plasma glucose levels in HFD-fed obese mice while increasing energy expenditure .
Celastrol, a plant-derived quinone methide triterpenoid, reportedly possesses preventative and therapeutic properties in attenuating metabolic dysregulations like obesity through anti-oxidative and anti-inflammatory activities . Additionally, celastrol administration enhanced systemic insulin sensitivity in HFD-fed obese rats, attenuated inflammatory responses and macrophage polarization in adipose tissues, improved skeletal muscle mitochondrial functions, and stimulated muscle mitochondrial biogenesis. In HFD-obese mice, celastrol has also been able to reduce intensinal lipid transporters and absorption; findings from this study also suggest that gut microbiota composition is critical in mediating the anti-obesity effects of celastrol .
The milestone efficacies achieved by semaglutide and other newly-developed anti-obesity medications will hopefully encourage the further development of effective therapies against obesity. With these advancements, it is more likely than ever that pharmacological therapies will achieve comparable efficacy with weight loss surgeries in the future. Although preclinical research has led to groundbreaking discoveries in this field, clinical testing, especially in diverse populations, will be required to evaluate drug efficacy and safety in humans.
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