GPR43 Potentiates β-Cell Function in Obesity

McNelis, Joanne; Lee, Yun Sok; Mayoral, Rafael; Kant, Rik van der; Johnson, Andrew M.; Wollam, Joshua; Olefsky, Jerrold M.

doi:10.2337/db14-1938

Cited by 168 publications

(235 citation statements)

References 43 publications

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“…Likewise, several genes important for normal beta cell function and maintaining beta cell mass have been detected using knock-out mice [139][140][141][142]. Often knock-out mice are subjected to a high fat diet to ascertain whether the gene of interest can compensate for an insulin-resistant state [143,144].…”

Section: Genetic Manipulation: Methods To Understand Insulin Resistanmentioning

confidence: 99%

Animal models for diabetes: Understanding the pathogenesis and finding new treatments

King

Bowe

2016

Biochemical Pharmacology

126

109

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Section: Genetic Manipulation: Methods To Understand Insulin Resistanmentioning

confidence: 99%

Animal models for diabetes: Understanding the pathogenesis and finding new treatments

King

Bowe

2016

Biochemical Pharmacology

126

109

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“…FFAR2-induced Ca 2+ signaling has been associated with obesity (8). Hence, the modulation of this pathway by the FFAR2-FFAR3 heteromer may have important physiologic implications.…”

Section: Resultsmentioning

confidence: 99%

“…Future studies will need to account for the possibility that the disease phenotypes ( e.g. , obesity, colitis, colon cancer, asthma, and arthritis) observed in mice upon the single knockout of either FFAR2 or FFAR3 (3–20) may be due to the concomitant loss of the heteromer and its unique signaling output. In fact, the association of both FFAR2- and FFAR3-knockout mice with the same colitis phenotype (10–16) is consistent with a FFAR2-FFAR3 heteromer-mediated mechanism that was lost upon the knockout of either receptor subunit.…”

Section: Discussionmentioning

confidence: 99%

“…The genetic deletion of either FFAR2 or FFAR3 expression in mice was found to either exacerbate or reduce a number of inflammatory diseases. Studies have implicated FFAR2 in diabetes (3), obesity (4–9), colitis (10–16), colon cancer (17), and arthritis (10); FFAR3 has been implicated in diabetes (3), colitis (14), hypertension (18), and asthma (19). …”

mentioning

confidence: 99%

“…For example, a peptide drug designed to specifically disrupt D 1 -D 2 dopamine heteromer has been shown to act as an antidepressant (26). A putative FFAR2-FFAR3 heteromer may mediate the disease phenotypes observed in FFAR2/3 single-knockout studies (3–20) because the knockout of either FFAR2 or FFAR3 would lead to the loss of the heteromer and any heteromer-dependent functions.…”

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confidence: 99%

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FFAR2‐FFAR3 receptor heteromerization modulates short‐chain fatty acid sensing

Ang

Xiong

et al. 2017

FASEB j.

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Free fatty acid receptors 2 and 3 (FFAR2/FFA2/GPR43 and FFAR3/FFA3/GPR41) are mammalian receptors for gut microbiota–derived short-chain fatty acids (SCFAs). These receptors are promising drug targets for obesity, colitis, colon cancer, asthma, and arthritis. Here, we demonstrate that FFAR2 and FFAR3 interact to form a heteromer in primary human monocytes and macrophages via proximity ligation assay, and during heterologous expression in HEK293 cells via bimolecular fluorescence complementation and fluorescence resonance energy transfer. The FFAR2-FFAR3 heteromer displayed enhanced cytosolic Ca2+ signaling (1.5-fold increase relative to homomeric FFAR2) and β-arrestin-2 recruitment (30-fold increase relative to homomeric FFAR3). The enhanced heteromer signaling was attenuated by FFAR2 antagonism (CATPB), Gαq inhibition (YM254890), or Gαi inhibition (pertussis toxin). Unlike homomeric FFAR2/3, the heteromer lacked the ability to inhibit cAMP production but gained the ability to induce p38 phosphorylation in HEK293 and inflammatory monocytes via a CATPB- and YM254890-sensitive mechanism. Our data, taken together, reveal that FFAR2 and FFAR3 may interact to form a receptor heteromer with signaling that is distinct from the parent homomers—a novel pathway for drug targeting.—Ang, Z., Xiong, D., Wu, M., Ding, J. L. FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing.

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Therapeutic Effects of Butyrate on Pediatric Obesity

et al. 2022

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ImportanceThe pediatric obesity disease burden imposes the necessity of new effective strategies.ObjectiveTo determine whether oral butyrate supplementation as an adjunct to standard care is effective in the treatment of pediatric obesity.Design, Setting, and ParticipantsA randomized, quadruple-blind, placebo-controlled trial was performed from November 1, 2020, to December 31, 2021, at the Tertiary Center for Pediatric Nutrition, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy. Participants included children aged 5 to 17 years with body mass index (BMI) greater than the 95th percentile.InterventionsStandard care for pediatric obesity supplemented with oral sodium butyrate, 20 mg/kg body weight per day, or placebo for 6 months was administered.Main Outcomes and MeasuresThe main outcome was the decrease of at least 0.25 BMI SD scores at 6 months. The secondary outcomes were changes in waist circumference; fasting glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, ghrelin, microRNA-221, and interleukin-6 levels; homeostatic model assessment of insulin resistance (HOMA-IR); dietary and lifestyle habits; and gut microbiome structure. Intention-to-treat analysis was conducted.ResultsFifty-four children with obesity (31 girls [57%], mean [SD] age, 11 [2.91] years) were randomized into the butyrate and placebo groups; 4 were lost to follow-up after receiving the intervention in the butyrate group and 2 in the placebo group. At intention-to-treat analysis (n = 54), children treated with butyrate had a higher rate of BMI decrease greater than or equal to 0.25 SD scores at 6 months (96% vs 56%, absolute benefit increase, 40%; 95% CI, 21% to 61%; P &lt; .01). At per-protocol analysis (n = 48), the butyrate group showed the following changes as compared with the placebo group: waist circumference, −5.07 cm (95% CI, −7.68 to −2.46 cm; P &lt; .001); insulin level, −5.41 μU/mL (95% CI, −10.49 to −0.34 μU/mL; P = .03); HOMA-IR, −1.14 (95% CI, −2.13 to −0.15; P = .02); ghrelin level, −47.89 μg/mL (95% CI, −91.80 to −3.98 μg/mL; P &lt; .001); microRNA221 relative expression, −2.17 (95% CI, −3.35 to −0.99; P &lt; .001); and IL-6 level, −4.81 pg/mL (95% CI, −7.74 to −1.88 pg/mL; P &lt; .001). Similar patterns of adherence to standard care were observed in the 2 groups. Baseline gut microbiome signatures predictable of the therapeutic response were identified. Adverse effects included transient mild nausea and headache reported by 2 patients during the first month of butyrate intervention.Conclusions and RelevanceOral butyrate supplementation may be effective in the treatment of pediatric obesity.Trial RegistrationClinicalTrials.gov Identifier: NCT04620057

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GPR43 Potentiates β-Cell Function in Obesity

Cited by 168 publications

References 43 publications

Animal models for diabetes: Understanding the pathogenesis and finding new treatments

Animal models for diabetes: Understanding the pathogenesis and finding new treatments

FFAR2‐FFAR3 receptor heteromerization modulates short‐chain fatty acid sensing

Therapeutic Effects of Butyrate on Pediatric Obesity

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