RESEARCH NEWS STORY
8 March 2023
Glucose-Dependent Insulinotropic Polypeptide Prevents Diet-Induced Obesityin MiceResearchers discover the mechanism of inhibition of diet-induced obesity in mice by the
glucose-dependent insulinotropic polypeptide “GIPFA-085”
The hormone glucose-dependent insulinotropic polypeptide (GIP) is considered obesogenic.
In contrast, GIP receptor agonists (GIPRAs) have shown reduced feeding and body weightin an obese mouse model. Therefore, the precise effects exerted by GIP and GIPRAs remainelusive. Recently, researchers demonstrated acute feeding inhibition and lowered bodyweight in mice with diet-induced obesity treated with GIPFA-085, a long-acting GIPRA. Theirfindings provide a scientific basis for GIP therapy for diabetes and obesity.
Obesity, type 2 diabetes, and their associated comorbidities contribute to millions of deaths
across the globe every year. While lifestyle interventions can decrease the progression ofthese diseases, there is a distinct lack of proven and safe treatments for obesity. Glucosedependent insulinotropic polypeptide (GIP) is an incretin hormone released by the smallintestine that stimulates insulin secretion upon eating food. While some researchers haveshown that GIP promotes obesity, others have presented contradictory evidence that GIP
receptor agonists (GIPRAs), which essentially have the same function as GIP, prevent thedisease. Therefore, there is a need to clarify the mechanisms and effects of GIP and GIPRA on
body weight and feeding.
Recently, researchers from Japan were able to demonstrate that GIPFA-085, a long-acting
GIPRA, acutely inhibited feeding and lowered the body weight of diet-induced obese (DIO)
mice in a sustained manner. Dr. Toshihiko Yada from Kansai Electric Power Medical ResearchInstitute and Gifu University Graduate School of Medicine led the research team that madethis important discovery, which has been published in Diabetes, Obesity and Metabolism. Theteam also consisted of Dr. Wanxin Han and Dr. Daisuke Yabe from Gifu University's Graduate
School of Medicine and Center for One Medicine Innovative Translational Research and Dr.
Yutaka Seino from Kansai Electric Power Hospital.
Says Dr. Yada, who is the corresponding author of the study, “GIP has been consideredobesogenic by some researchers. In contrast, GIPRAs, alone and in combination withglucagon-like peptide-1 (GLP-1) receptor agonists, reportedly reduce feeding and body weightin diet-induced obese (DIO) mice. In this regard, this study aimed to clarify the effects of GIPRA
on feeding and body weight.”
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 synthesized 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. Yabe remarks, “A daily dose ofGIPFA-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 wasevident in DIO mice but not in ob/ob mice.”
In addition, the injected GIPFA-085 demonstrated the coordination of the satiety-signaling
leptin with the murine central nervous system through the regulation of intracellular calcium
concentration ([Ca2+]i). GIPFA-085 inhibited feeding and sustainedly lowered body weight inDIO mice via an increase in leptin and activation of the satiety neurons in the hypothalamicarcuate 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 foodintake,” says Dr. Seino.
In summary, by demonstrating the therapeutic potential of GIPRAs in a mouse model, thisstudy could facilitate the development of GIP/GLP-1 dual agonists to treat diabetes andobesity. The study also provides an avenue for novel incretin-GIP-based therapy.
“By demonstrating the therapeutic potential of GIPRAs, our study could lead to an increased
quality of life in patients with diabetes and obesity. Our study also provides hope to several
patients with obesity, who are suffering from a lack of safe and effective treatment for thedisorder,” concludes Dr. Yada.

Reference
Authors

Wanxin Han1,2,3, Lei Wang1,2,3, Kento Ohbayashi4, Masakazu
Takeuchi5, Libbey O’Farrell6, Tamer Coskun6, Yermek Rakhat1,2,3,Daisuke Yabe2,7,8, Yusaku Iwasaki4, Yutaka Seino7 and Toshihiko
Yada1,2,3

Title of original paper

Glucose-dependent insulinotropic polypeptide counteracts dietinduced obesity along with reduced feeding, elevated plasma leptin
and activation of leptin-responsive and proopiomelanocortin
neurons in the arcuate nucleus

JournalDiabetes, Obesity and Metabolism

DOI

10.1111/dom.15001

Affiliations

Latest article publication date
Method of research
Subject of research
COI statement

1Center for Integrative Physiology, Kansai Electric Power Medical
Research Institute, Kyoto 604-8436, Japan2
DepartmentofDiabetes,
Endocrinology
andMetabolism/Rheumatology and Clinical Immunology, Gifu
University Graduate School of Medicine, Gifu 501-1194, Japan
3
Division of Diabetes, Metabolism and Endocrinology, Kobe
University Graduate School of Medicine, Kobe 650-0047, Japan
4Laboratory of Animal Science, Graduate School of Life andEnvironmental Sciences, Kyoto Prefectural University, Kyoto 6068522, Japan
5
Eli Lilly Japan, Kobe 651-0086, Japan
6
Eli Lilly Company, Indianapolis IN 46285, USA
7
Yutaka Seino Distinguished Center for Diabetes Research, Kansai
Electric Power Hospital, Osaka 553-0003, Japan
8Center for One Medicine Innovative Translational Research, Gifu
University Institute for Advanced Study, Gifu, Japan
28 February 2023
Experimental study
Animals
T.Y. received grant support from Eli Lilly Company Co. Eli Lilly
Company Co. provided GIPFA-085.

Image title: Role of glucose-dependent insulinotropic polypeptide (GIP) in preventing dietinduced obesity in a mouse modelImage caption: The mechanism of GIPFA-085-mediated inhibition of diet-induced obesity inmice shows that GIPs have therapeutic potential in treating obesity and diabetes
Image Credit: Toshihiko Yada from Gifu University
Image Source Link to be added in the Image Credit Section of EA form: Not applicable
License type: Original content
About Professor Toshihiko YadaToshihiko Yada is currently serving as the Director of the Center for Integrative Physiology,
Division of Integrative Physiology, Kansai Electric Power Medical Research Institute and as a
Professor at Gifu University Graduate School of Medicine’s Department of Diabetes,
Endocrinology and Metabolism. Dr. Yada’s research primarily focuses on uncovering the causeof obesity and type 2 diabetes and developing novel treatments for these two diseases. Dr.
Yada has published his work in several reputed journals. He has over 300 publications andmore than 13,000 citations to his credit.