Preventing diet-induced obesity in mice
Posted: 21 March 2023 | Izzy Wood (Drug Target Review) | No comments yet
Japanese researchers discover the mechanism of inhibition of diet-induced obesity in mice by the glucose-dependent insulinotropic polypeptide
Researchers from Gifu University, Japan, were able to demonstrate that GIPFA-085, a long-acting GIP receptor agonists (GIPRAs), acutely inhibited feeding and lowered the body weight of diet-induced obese (DIO) mice in a sustained manner.
The hormone glucose-dependent insulinotropic polypeptide (GIP) is considered obesogenic. In contrast, GIPRAs have shown reduced feeding and body weight in an obese mouse model. Therefore, the precise effects exerted by GIP and GIPRAs remain elusive.
The new study, published in Diabetes, Obesity and Metabolism, demonstrated acute feeding inhibition and lowered body weight in mice with diet-induced obesity treated with GIPFA-085, a long-acting GIPRA. Their findings provide a scientific basis for GIP therapy for diabetes and obesity.
GIP is an incretin hormone released by the small intestine that stimulates insulin secretion upon eating food. While some researchers have shown that GIP promotes obesity, others have presented contradictory evidence that GIPRAs, which essentially have the same function as GIP, prevent the disease. Therefore, there is a need to clarify the mechanisms and effects of GIP and GIPRA on body weight and feeding.
“GIP has been considered obesogenic by some researchers. In contrast, GIPRAs, alone and in combination with glucagon-like peptide-1 (GLP-1) receptor agonists, reportedly reduce feeding and body weight in diet-induced obese (DIO) mice. In this regard, this study aimed to clarify the effects of GIPRA on feeding and body weight,” said Dr Toshihiko Yada from Kansai Electric Power Medical Research Institute and Gifu University Graduate School of Medicine.
The team examined the short- and long-term effects of subcutaneous GIPFA-085 on measurable biological parameters such as blood glucose, food intake, body weight, respiratory exchange ratio, and plasma leptin levels in DIO mice.
They also conducted similar experiments on ob/ob mice that were genetically programmed to exhibit leptin dysfunction. Leptin—a hormone synthesised by fat cells—controls satiety and energy storage by providing feedback to the central nervous system.
The administered GIPFA-085 doses were as low as 30 nmol/kg or as high as 300 nmol/kg during these murine experiments. The team found that a single dose (30–300 nmol/kg) of subcutaneously injected GIPFA-085 reduced blood glucose, elevated plasma leptin levels at 0.5–6 h, and inhibited food intake at 2–24 h in DIO mice.
Dr Daisuke Yabe from Gifu University’s Graduate School of Medicine and Centre for One Medicine Innovative Translational Research explained: “A daily dose of GIPFA-085 (300 nmol/kg) not only inhibited food intake but also increased fat utilization on day 1, and reduced body weight gain on days 3–12 of the treatment. This observation was evident in DIO mice but not in ob/ob mice.”
In addition, the injected GIPFA-085 demonstrated the coordination of the satiety-signalling leptin with the murine central nervous system through the regulation of intracellular calcium concentration ([Ca2+]i). GIPFA-085 inhibited feeding and sustained lowered body weight in DIO mice via an increase in leptin and activation of the satiety neurons in the hypothalamic arcuate nucleus (ARC).
GIPFA-085 increased [Ca2+]i in the ARC leptin-responsive and proopiomelanocortin (POMC) neurons. GIPFA-085 and leptin cooperated to increase [Ca2+]i in ARC neurons and inhibit food intake, as understood by Dr Yutaka Seino from Kansai Electric Power Hospital.
In summary, by demonstrating the therapeutic potential of GIPRAs in a mouse model, this study could facilitate the development of GIP/GLP-1 dual agonists to treat diabetes and obesity. The study also provides an avenue for novel incretin-GIP-based therapy.
Peptide Therapeutics, Proteomics, Targets
Centre for One Medicine Innovative Translational Research, Gifu University, Gifu University's Graduate School of Medicine, Kansai Electric Power Hospital.
Dr Daisuke Yabe, Dr Toshihiko Yada, Dr Yutaka Seino