The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

Secher, Anna; Jelsing, Jacob; Baquero, Arian F.; Hecksher‐Sørensen, Jacob; Cowley, Michael A.; Dalbøge, Louise S.; Hansen, Gitte; Grove, Kevin L.; Pyke, Charles; Raun, Kirsten; Schäffer, Lauge; Tang-Christensen, Mads; Verma, Saurabh; Witgen, Brent M.; Vrang, Niels; Knudsen, Lotte Bjerre

doi:10.1172/jci75276

Cited by 716 publications

(791 citation statements)

References 99 publications

(108 reference statements)

Supporting

Mentioning

725

Contrasting

Unclassified

Order By: Relevance

“…A previous study showed that the DPP4 activity levels in the hypothalamus decreased in monosodium glutamate-induced obese and fooddeprived animals compared with the controls (Alponti et al 2011), indicating that DPP4 may participate in the energy balance in the hypothalamus. Furthermore, GLP1R on POMC/CART-expressing ARC neurons in mice was suggested to be the primary factor mediating liraglutide-induced weight loss (Anna et al 2014). In our study, we found that GLP1R level is evaluated in the hypothalamus of diabetic rats with liraglutide.…”

Section: Figurementioning

confidence: 48%

“…Recently, growing evidence has indicated that liraglutide, a classical GLP1 analog, is effective in controlling glucose homeostasis, and reducing body weight and appetite (Cummings et al 2010, Anna et al 2014. However, administration of DPP4 inhibitors, which prolong the longevity of native GLP1, results in only negligible weight loss (Raun et al 2007, Niswender et al 2013.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Liraglutide alters DPP4 in the circumvallate papillae of type 2 diabetic rats

Cao¹,

Zhou²,

Liu³

et al. 2016

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Liraglutide, a human glucagon-like peptide (GLP1) analog that partially inhibits dipeptidyl-peptidase 4 (DPP4), can decrease glucose levels and suppress appetite in patients with type 2 diabetes (T2DM). GLP1 and its receptor (GLP1R) also exist in the taste buds of rodents and regulate taste sensitivity. DPP4, a protease, functions in homeostasis of blood glucose, lipids, and body weight. Interactions among GLP1, GLP1R, and DPP4 likely affect taste and food-intake behavior. The aim of the present study was to investigate DPP4 expression in the taste buds of the circumvallate papillae (CV) in T2DM rats, and determine the effects of liraglutide treatment. Rats were divided into diabetic control (T2DM-C), normal control (NC), and liraglutide-treated diabetic (T2DM + LIR) groups. DPP4 localization and gene expression levels were evaluated by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (RT-qPCR), respectively. DPP4 immunoreactive cells were localized in the taste buds of the rat CV. RT-qPCR showed significantly higher expression of Dpp4 mRNA in both the taste buds and hypothalamus of T2DM-C rats compared with NC rats. However, in the T2DM + LIR group, Dpp4 expression differed between the taste buds and hypothalamus, with significantly higher and lower levels compared with the T2DM-C group, respectively. Dpp4 mRNA expression is increased in the taste buds of the CV of T2DM rats. Liraglutide simultaneously upregulated (taste buds) and downregulated (hypothalamus) Dpp4 expression in T2DM rats. Therefore, DPP4 may be closely associated with the anorexigenic signaling and weight loss induced by the treatment of liraglutide in type 2 diabetic patients.

show abstract

Section: Figurementioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Liraglutide alters DPP4 in the circumvallate papillae of type 2 diabetic rats

Cao¹,

Zhou²,

Liu³

et al. 2016

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

show abstract

“…We can therefore not exclude that liraglutide also affects activation in the hypothalamus. The effects of liragluitde in the hypothalamus have been shown in rodents (29), but further research is needed to investigate this issue in humans.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, it might exert its effect on the CNS by direct activation of central GLP-1 receptors (12). Indeed, it was shown that GLP-1 receptors in the CNS are required for the anorectic and weight-reducing effects of liraglutide (29). However, results from studies in rodents and humans indicate that an indirect route of action, involving intestinal vagal afferents where GLP-1 receptors are present, may also be important (31).…”

Section: Resultsmentioning

confidence: 99%

Liraglutide Reduces CNS Activation in Response to Visual Food Cues Only After Short-term Treatment in Patients With Type 2 Diabetes

et al. 2015

View full text Add to dashboard Cite

OBJECTIVEGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with reduced appetite and body weight. We investigated whether these effects could be mediated by the central nervous system (CNS). RESEARCH DESIGN AND METHODSWe performed a randomized crossover study in obese patients with type 2 diabetes (n = 20, mean age 59.3 6 4.1 years, mean BMI 32 6 4.7 kg/m 2 ), consisting of two periods of 12-week treatment with either liraglutide 1.8 mg or insulin glargine. Using functional MRI, we determined the effects of treatment on CNS responses to viewing food pictures in the fasted condition and 30 min after meal intake. RESULTSAfter 12 weeks, the decrease in HbA 1c was larger with liraglutide versus insulin glargine (D20.7% vs. 20.2%, P < 0.001). Body weight decreased during liraglutide versus insulin glargine (D23.3 kg vs. 0.8 kg, P < 0.001). After 10 days, patients treated with liraglutide, compared with insulin glargine, showed decreased responses to food pictures in insula and putamen (P £ 0.02). In addition, liraglutide enhanced the satiating effect of meal intake on responses in putamen and amygdala (P £ 0.05). Differences between liraglutide and insulin glargine were not observed after 12 weeks. CONCLUSIONSCompared with insulin, liraglutide decreased CNS activation significantly only after short-term treatment, suggesting that these effects of GLP-1RA on the CNS may contribute to the induction of weight loss, but not necessarily to its maintenance, in view of the absence of an effect of liraglutide on CNS activation in response to food pictures after longer-term treatment.Obesity and diabetes constitute a major health burden due to their pandemic occurrence (1) and their association with adverse consequences, such as cardiovascular disease (2). Obesity is the result of a long-term excess energy intake relative to expenditure, leading to increased weight and body fat mass. The central nervous system (CNS) has a major role in the regulation of food intake and the maintenance

show abstract

“…7,8,20 In the db/db time study a weightadjusted dose of 804 mg/kg (160 nmol/kg) was used. Vehicle controls were injected with 200 ml 1 X DPBS.…”

Section: Probing Of Mice and Preparation For Histologymentioning

confidence: 99%

Beta cell specific probing with fluorescent exendin-4 is progressively reduced in type 2 diabetic mouse models

Lehtonen

Schäffer

Rasch

et al. 2015

Islets

Self Cite

View full text Add to dashboard Cite

Probes based on GLP-1R agonist exendin-4 have shown promise as in vivo b cell tracers. However, questions remain regarding the b cell specificity of exendin-4 probes, and it is unclear if the expression levels of the GLP-1R are affected in a type 2 diabetic state. Using in vivo probing followed by ex vivo imaging we found fluorescent exendin-4 probes to distinctly label the pancreatic islets in mice in a Glp-1r dependent manner. Furthermore, a co-localization study revealed a near 100 percent b cell specificity with less than one percent probing in other analyzed cell types. We then tested if probing was affected in models of type 2 diabetes using the Lepr db/db (db/db) and the Diet-Induced Obese (DIO) mouse. Although nearly all b cells continued to be probed, we observed a progressive decline in probing intensity in both models with the most dramatic reduction seen in db/db mice. This was paralleled by a progressive decrease in Glp-1r protein expression levels. These data confirm b cell specificity for exendin-4 based probes in mice. Furthermore, they also suggest that GLP-1R targeting probes may provide a tool to monitor b cell function rather than mass in type 2 diabetic mouse models.

show abstract

The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

Cited by 716 publications

References 99 publications

Liraglutide alters DPP4 in the circumvallate papillae of type 2 diabetic rats

Liraglutide alters DPP4 in the circumvallate papillae of type 2 diabetic rats

Liraglutide Reduces CNS Activation in Response to Visual Food Cues Only After Short-term Treatment in Patients With Type 2 Diabetes

Beta cell specific probing with fluorescent exendin-4 is progressively reduced in type 2 diabetic mouse models

Contact Info

Product

Resources

About