bims-mimead 2024-11-17 papers

bims-mimead

Biomed News

on Mitochondrial metabolism in ageing and metabolic disease

Issue of 2024–11–17
fourteen papers selected by
Rachel M. Handy, University of Guelph

The Relation Between Mitochondrial Membrane Potential and Reactive Oxygen Species Formation.
High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis.
The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.
Interactions between glucagon like peptide 1 (GLP-1) and estrogens regulates lipid metabolism.
GLP-1 receptor agonists: a magic bullet for obesity?
Rapid downregulation of DICER is a hallmark of adipose tissue upon high-fat diet feeding.
NK2R control of energy expenditure and feeding to treat metabolic diseases.
Adipokines: masterminds of metabolic inflammation.
Rosiglitazone-induced white adipocyte browning is regulated by actin and Myh9.
Daily GDF15 treatment has sex-specific effects on body weight and food intake and does not enhance the effects of voluntary physical activity in mice.
Annual Prize Lecture 2024: Endogenous physiological mechanisms as basis for the treatment of obesity and type 2 diabetes.
ZnR/GPR39 regulates hepatic insulin signaling, tunes liver bioenergetics and ROS production, and mitigates liver fibrosis and injury.
The effect of small increases in blood glucose on insulin secretion and endogenous glucose production in humans.
Medium-chain fatty acid receptor GPR84 deficiency leads to metabolic homeostasis dysfunction in mice fed high-fat diet.

Methods Mol Biol. 2025 ;2878 133-162

The Relation Between Mitochondrial Membrane Potential and Reactive Oxygen Species Formation.

Magdalena Lebiedzinska-Arciszewska, Jan Suski, Massimo Bonora, Barbara Pakula, Paolo Pinton, Jerzy Duszynski, Patrycja Jakubek-Olszewska, Mariusz R Wieckowski.

  Mitochondria are considered one of the main sites of reactive oxygen species (ROS) production in the eukaryotic cells. For this reason, mitochondrial dysfunction associated with increased ROS production underlies various pathological conditions as well as promotes aging. Chronically increased rates of ROS production contribute to oxidative damage to macromolecules, i.e., DNA, proteins, and lipids. Accumulation of unrepaired oxidative damage may result in progressive cell dysfunction, which can finally trigger cell death. The main by-product of mitochondrial oxidative phosphorylation is superoxide, which is generated by the leak of electrons from the mitochondrial respiratory chain complexes leading to one-electron reduction of oxygen. Mitochondrial superoxide dismutase (MnSOD, SOD2) as well as cytosolic superoxide dismutase (Cu/ZnSOD, SOD1), whose smaller pool is localized in the mitochondrial intermembrane space, converts superoxide to H2O2, which can be then degraded by the catalase to harmless H2O.In this chapter, we focus on the relationship between one of the bioenergetic parameters, which is mitochondrial membrane potential, and the rate of ROS formation. We present a set of various methods enabling the characterization of these parameters applicable to isolated mitochondria or intact cells. We also present examples of experimental data demonstrating that the magnitude and direction (increase or decrease) of a change in mitochondrial ROS production depend on the mitochondrial metabolic state.

Keywords:  Confocal microscopy; Hydrogen peroxide; Mitochondria; Oxygen consumption; Resazurin; Superoxide

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_8
iScience. 2024 Nov 15. 27(11): 111175

High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis.

Leigh Goedeke, Jordan W Strober, Rebecca Suh, Lauren M Paolella, Xiruo Li, Jillian C Rogers, Max C Petersen, Ali R Nasiri, Gregori Casals, Mario Kahn, Gary W Cline, Varman T Samuel, Gerald I Shulman, Daniel F Vatner.

  Hepatic insulin resistance (IR) is often said to be "pathway-selective" with preserved insulin stimulation of de novo lipogenesis (DNL) despite attenuated insulin signaling toward glucose metabolism. However, DNL has not been assessed in models of liver-specific IR. We studied mice with differential tissue-specific lipid-induced IR achieved by different durations of high-fat diet (HFD) feeding. Mice with isolated hepatic IR demonstrated markedly reduced DNL, with a rebound seen in mice with whole-body IR. Insr T1150A mice (protected against diacylglycerol-PKCε-induced hepatic IR) maintained normal DNL with HFD feeding. During hyperinsulinemic clamps, hepatic IR reduced DNL, but hyperglycemia augmented DNL in both resistant and sensitive animals. Regulation through SREBP1c did not consistently correlate with changes in DNL. These results demonstrate that hepatic IR is not pathway-selective, highlighting the primacy of lipogenic substrate in stimulation of DNL. Future therapeutics to reduce lipogenesis should target substrate drivers of DNL rather than targeting plasma insulin levels.

Keywords:  Developmental biology; Stem cells research; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.111175
Nat Commun. 2024 Nov 13. 15(1): 9826

The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.

Tang Cam Phung Pham, Steffen Henning Raun, Essi Havula, Carlos Henriquez-Olguín, Diana Rubalcava-Gracia, Emma Frank, Andreas Mæchel Fritzen, Paulo R Jannig, Nicoline Resen Andersen, Rikke Kruse, Mona Sadek Ali, Andrea Irazoki, Jens Frey Halling, Stine Ringholm, Elise J Needham, Solvejg Hansen, Anders Krogh Lemminger, Peter Schjerling, Maria Houborg Petersen, Martin Eisemann de Almeida, Thomas Elbenhardt Jensen, Bente Kiens, Morten Hostrup, Steen Larsen, Niels Ørtenblad, Kurt Højlund, Michael Kjær, Jorge L Ruas, Aleksandra Trifunovic, Jørgen Frank Pind Wojtaszewski, Joachim Nielsen, Klaus Qvortrup, Henriette Pilegaard, Erik Arne Richter, Lykke Sylow.

Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.

DOI: https://doi.org/10.1038/s41467-024-54183-4
Biochem Pharmacol. 2024 Nov 13. pii: S0006-2952(24)00623-3. [Epub ahead of print]230(Pt 3): 116623

Interactions between glucagon like peptide 1 (GLP-1) and estrogens regulates lipid metabolism.

Jorge F A Model, Rafaella S Normann, Éverton L Vogt, Maiza Von Dentz, Marjoriane de Amaral, Rui Xu, Tsvetan Bachvaroff, Poli Mara Spritzer, J Sook Chung, Anapaula S Vinagre.

  Obesity, characterized by excessive fat accumulation in white adipose tissue (WAT), is linked to numerous health issues, including insulin resistance (IR), and type 2 diabetes mellitus (DM2). The distribution of adipose tissue differs by sex, with men typically exhibiting android adiposity and pre-menopausal women displaying gynecoid adiposity. After menopause, women have an increased risk of developing android-type obesity, IR, and DM2. Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are important in treating obesity and DM2 by regulating insulin secretion, impacting glucose and lipid metabolism. GLP-1Rs are found in various tissues including the pancreas, brain, and adipose tissue. Studies suggest GLP-1RAs and estrogen replacement therapies have similar effects on tissues like the liver, central nervous system, and WAT, probably by converging pathways involving protein kinases. To investigate these interactions, female rats underwent ovariectomy (OVR) to promote a state of estrogen deficiency. After 20 days, the rats were euthanized and the tissues were incubated with 10 μM of liraglutide, a GLP-1RA. Results showed significant changes in metabolic parameters: OVR increased lipid catabolism in perirenal WAT and basal lipolysis in subcutaneous WAT, while liraglutide treatment enhanced stimulated lipolysis in subcutaneous WAT. Liver responses included increased stimulated lipolysis with liraglutide. Transcriptome analysis revealed distinct gene expression patterns in WAT of OVR rats and those treated with GLP-1RA, highlighting pathways related to lipid and glucose metabolism. Functional enrichment analysis showed estrogen's pivotal role in these pathways, influencing genes involved in lipid metabolism regulation. Overall, the study underscores GLP-1RA acting directly on adipose tissues and highlights the complex interactions between GLP-1 and estrogen in regulating metabolism, suggesting potential synergistic therapeutic effects in treating metabolic disorders like obesity and DM2.

Keywords:  Estrogens; GLP-1; Incretins; Menopause; Ovariectomy

DOI:  https://doi.org/10.1016/j.bcp.2024.116623
Lancet Reg Health West Pac. 2024 Oct;51 101233

GLP-1 receptor agonists: a magic bullet for obesity?

The Lancet Regional Health-Western Pacific.

DOI: https://doi.org/10.1016/j.lanwpc.2024.101233
Mol Cell Endocrinol. 2024 Nov 12. pii: S0303-7207(24)00269-7. [Epub ahead of print]595 112413

Rapid downregulation of DICER is a hallmark of adipose tissue upon high-fat diet feeding.

Søren Madsen, A Augusto Peluso, Caio Y Yonamine, Lars R Ingerslev, Morten Dall, Patricia S S Petersen, Kaja Plucinska, Marta Pradas-Juni, Roger Moreno-Justicia, Alba Gonzalez-Franquesa, Kurt Højlund, Jan-Wilhelm Kornfeld, Brice Emanuelli, Sara G Vienberg, Jonas T Treebak.

  Adipose tissue regulates whole-body energy balance and is crucial for metabolic health. With energy surplus, adipose tissue expands, which may lead to local areas of hypoxia and inflammation, and consequently impair whole-body insulin sensitivity. We report that DICER, a key enzyme for miRNA maturation, is significantly lower in abdominal subcutaneous white adipose tissue of men with obesity compared with men with a lean phenotype. Furthermore, DICER is profoundly downregulated in mouse adipose tissue and liver within the first week on a high-fat diet (HFD), and remains low after prolonged HFD feeding. Downregulation of DICER in mice occurs in both mature adipocytes and stromal vascular cells. Mechanistically, chemically induced hypoxia in vitro shows DICER degradation via interaction with hypoxia-inducible factor 1-α (HIF1α). Moreover, DICER and HIF1α interact in brown adipose tissue post-HFD which may signal for DICER degradation. Finally, RNA sequencing reveals a striking time-dependent downregulation of total miRNA content in mouse subcutaneous adipose tissue after HFD feeding. Collectively, HFD in mice reduces adipose tissue DICER, likely due to hypoxia-induced interaction with HIF1α during tissue expansion, and this significantly impacts miRNA content.

Keywords:  DICER; HIF1α; High-fat diet; Human adipose tissue; Hypoxia; Mouse adipose tissue; miRNA

DOI:  https://doi.org/10.1016/j.mce.2024.112413
Nature. 2024 Nov 13.

NK2R control of energy expenditure and feeding to treat metabolic diseases.

Frederike Sass, Tao Ma, Jeppe H Ekberg, Melissa Kirigiti, Mario G Ureña, Lucile Dollet, Jenny M Brown, Astrid L Basse, Warren T Yacawych, Hayley B Burm, Mette K Andersen, Thomas S Nielsen, Abigail J Tomlinson, Oksana Dmytiyeva, Dan P Christensen, Lindsay Bader, Camilla T Vo, Yaxu Wang, Dylan M Rausch, Cecilie K Kristensen, María Gestal-Mato, Wietse In Het Panhuis, Kim A Sjøberg, Stace Kernodle, Jacob E Petersen, Artem Pavlovskyi, Manbir Sandhu, Ida Moltke, Marit E Jørgensen, Anders Albrechtsen, Niels Grarup, M Madan Babu, Patrick C N Rensen, Sander Kooijman, Randy J Seeley, Anna Worthmann, Joerg Heeren, Tune H Pers, Torben Hansen, Magnus B F Gustafsson, Mads Tang-Christensen, Tuomas O Kilpeläinen, Martin G Myers, Paul Kievit, Thue W Schwartz, Jakob B Hansen, Zachary Gerhart-Hines.

The combination of decreasing food intake and increasing energy expenditure represents a powerful strategy for counteracting cardiometabolic diseases such as obesity and type 2 diabetes1. Yet current pharmacological approaches require conjugation of multiple receptor agonists to achieve both effects2-4, and so far, no safe energy-expending option has reached the clinic. Here we show that activation of neurokinin 2 receptor (NK2R) is sufficient to suppress appetite centrally and increase energy expenditure peripherally. We focused on NK2R after revealing its genetic links to obesity and glucose control. However, therapeutically exploiting NK2R signalling has previously been unattainable because its endogenous ligand, neurokinin A, is short-lived and lacks receptor specificity5,6. Therefore, we developed selective, long-acting NK2R agonists with potential for once-weekly administration in humans. In mice, these agonists elicit weight loss by inducing energy expenditure and non-aversive appetite suppression that circumvents canonical leptin signalling. Additionally, a hyperinsulinaemic-euglycaemic clamp reveals that NK2R agonism acutely enhances insulin sensitization. In diabetic, obese macaques, NK2R activation significantly decreases body weight, blood glucose, triglycerides and cholesterol, and ameliorates insulin resistance. These findings identify a single receptor target that leverages both energy-expending and appetite-suppressing programmes to improve energy homeostasis and reverse cardiometabolic dysfunction across species.

DOI: https://doi.org/10.1038/s41586-024-08207-0
Nat Rev Immunol. 2024 Nov 07.

Adipokines: masterminds of metabolic inflammation.

Herbert Tilg, Gianluca Ianiro, Antonio Gasbarrini, Timon E Adolph.

Adipose tissue is an immunologically active organ that controls host physiology, partly through the release of mediators termed adipokines. In obesity, adipocytes and infiltrating leukocytes produce adipokines, which include the hormones adiponectin and leptin and cytokines such as tumour necrosis factor and IL-1β. These adipokines orchestrate immune responses that are collectively referred to as metabolic inflammation. Consequently, metabolic inflammation characterizes metabolic disorders and promotes distinct disease aspects, such as insulin resistance, metabolic dysfunction-associated liver disease and cardiovascular complications. In this unifying concept, adipokines participate in the immunological cross-talk that occurs between metabolically active organs in metabolic diseases, highlighting the fundamental role of adipokines in obesity and their potential for therapeutic intervention. Here, we summarize how adipokines shape metabolic inflammation in mice and humans, focusing on their contribution to metabolic disorders in the setting of obesity and discussing their value as therapeutic targets.

DOI: https://doi.org/10.1038/s41577-024-01103-8
Life Sci. 2024 Nov 05. pii: S0024-3205(24)00807-5. [Epub ahead of print]359 123217

Rosiglitazone-induced white adipocyte browning is regulated by actin and Myh9.

Lupeng Chen, Jingjie Hao, Junzhi Zhang, Jian Wu, Zhuqing Ren.

   AIMS: This study investigates the role of actin polymerization and Myh9 in mediating lipid droplet (LD) fission during rosiglitazone-induced browning of white adipocytes. The aim is to understand how LD splitting might contribute to the beige conversion of white adipose tissue, providing insights into adipocyte plasticity and metabolic regulation.
MATERIALS AND METHODS: C3H10 T1/2-differentiated adipocytes were used as a classical model to study white adipocyte browning. Rosiglitazone was applied to induce browning, and the interactions between LDs and actin, as well as the distribution of Myh9, were assessed using immunofluorescence and Western blotting. In vivo, we employed a microfilament inhibitor to block actin polymerization in cold-stimulated mice and evaluated changes in LD morphology and browning. Furthermore, dynamic live-cell imaging using confocal microscopy was conducted to observe the real-time behavior of LDs during the browning process and to determine whether they undergo fission.
MAIN FINDINGS: Our results demonstrate that rosiglitazone significantly induces LD size reduction, a process correlated with the increased contact of LDs with microfilaments. Inhibition of actin polymerization prevented both the reduction in LD size and the browning of white adipocytes, indicating that actin plays a critical role. Myh9 was enriched at the LD fission sites, forming a structure resembling a contractile ring. Overexpression of Myh9 promoted the shrinkage of LD, suggesting that it may be involved in LD fission.
SIGNIFICANCE: This study identifies actin and Myh9 as key regulators of LD fission in rosiglitazone-induced browning of white adipocytes, offering new insights into the cellular mechanisms of adipocyte plasticity. The findings propose a novel pathway by which LD dynamics contribute to the beige conversion of white fat, with potential implications for metabolic disease therapies targeting adipocyte function and energy expenditure.

Keywords:  Actin; Lipid droplet fission; Myh9; Rosiglitazone; Transdifferentiation

DOI:  https://doi.org/10.1016/j.lfs.2024.123217
J Physiol. 2024 Nov 09.

Daily GDF15 treatment has sex-specific effects on body weight and food intake and does not enhance the effects of voluntary physical activity in mice.

Stewart Jeromson, Michael Akcan, Bradley Baranowski, Meagan Arbeau, Annalaura Bellucci, David C Wright.

  Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that suppresses food intake and causes weight loss. GDF15 also reduces voluntary physical activity and, thus, it is not clear whether combining GDF15 with exercise will be beneficial or if reductions in food intake would be offset by decreases in physical activity. We investigated how GDF15 treatment combined with voluntary wheel running (VWR) would impact weight gain, food intake, adiposity and indices of metabolic health in mice. High-fat fed male and female mice underwent daily GDF15 treatments and were given access to voluntary running wheels, or not, for 11 days. In both sexes, VWR prevented weight gain. In males, GDF15 reduced food intake, as well as attenuated weight gain and the accumulation of adipose tissue, with no additional effect of VWR. In female mice, GDF15 did not impact body weight gain or body composition. GDF15 acutely reduced food intake in female mice but this was followed by a period of rebound hyperphagia and consequently GDF15 did not reduce total food intake in female mice. GDF15 treatment reduced wheel running distance in both sexes. There were main effects of VWR to improve glucose tolerance in female but not male mice. These findings show that GDF15 has sex-specific effects on food intake and consequently weight gain and adiposity. There is no added benefit of combining GDF15 and voluntary physical activity for weight loss. Adaptive responses to acute caloric restriction induced by GDF15 might limit its effectiveness as a weight loss tool in females. KEY POINTS: GDF15 is a stress-induced signalling factor that reduces food intake and voluntary physical activity. It is not known whether combining GDF15 treatment with voluntary wheel running would impart beneficial combined effects in attenuating weight gain and the accumulation of adipose tissue. In the present study, we demonstrate that GDF15 reduces food intake and prevents weight gain in male but not female mice consuming a high-fat diet and also that combining GDF15 with voluntary wheel running (VWR) does not lead to a greater dampening of weight gain. In female mice, GDF15 acutely reduced food intake, but this was followed by a period of rebound hyperphagia resulting in no differences in total food intake. In both sexes, VWR was equivalent, or superior to GDF15 in preventing weight gain.

Keywords:  GDF15; food intake; mice; obesity; physical activity

DOI:  https://doi.org/10.1113/JP287256
J Physiol. 2024 Nov 09.

Annual Prize Lecture 2024: Endogenous physiological mechanisms as basis for the treatment of obesity and type 2 diabetes.

Jens Juul Holst.

  In 1964, it was proven that postprandial insulin secretion is largely regulated by gut hormones and, in 1973, it was proposed that a gut hormone would also regulate appetite and food intake. Several gut hormones were tested for metabolic actions with disappointing results until the discovery of the proglucagon derivative, glucagon-like peptide-1 (GLP-1). This peptide from the distal intestine has preserved activity on insulin secretion in people with type 2 diabetes and turned out to regulate both secretion and motility in the gastrointestinal tract and importantly, appetite and food intake, thus functioning as an efficient 'ileal brake' hormone. However, the natural hormone acts predominantly via sensory afferent systems and is extremely rapidly removed from the circulation by enzymatic degradation and renal elimination, and increasing the doses merely results in nausea and vomiting. Lipidation of analogs turned out to provide both stability and limit renal elimination, and very slow up-titration of dosing improves tolerance. Indeed, the most recent agonists may near-normalize glycaemic control in type 2 diabetes, may cause weight losses of up to 25% of body weight, and significantly reduce cardiovascular risk, effects that resemble those of bariatric surgery. Thus, a solution to one of the most serious health problems of modern civilization, the increased morbidity and mortality of the metabolic syndrome, may be addressed by mobilization of one of the body's own regulatory mechanisms.

Keywords:  GLP‐1; diabetes; incretin; obesity; weight loss

DOI:  https://doi.org/10.1113/JP287461
Redox Biol. 2024 Oct 18. pii: S2213-2317(24)00381-1. [Epub ahead of print]78 103403

ZnR/GPR39 regulates hepatic insulin signaling, tunes liver bioenergetics and ROS production, and mitigates liver fibrosis and injury.

Anil Khushalrao Shendge, Israel Sekler, Michal Hershfinkel.

  Adequate supply of zinc is essential for hepatic function and its deficiency is associated with acute liver injury (ALI) and chronic nonalcoholic fatty liver disease (NAFLD). However, how zinc controls hepatic function is unknown. We found that the zinc sensitive ZnR/GPR39, a mediator of zinc signaling, enhances hepatic phosphorylation of ERK1/2, which is reduced in ZnR/GPR39 deficient livers. Surprisingly, livers from ZnR/GPR39 knockout (KO) mice exhibited elevated insulin receptor expression and downstream AKT activation. Moreover, ZnR/GPR39 KO mice had higher blood fasting glucose level, pronounced hepatic lipid accumulation, increased hepatocyte oxygen consumption rate (OCR) and reactive oxygen species (ROS) levels. These data suggest that ZnR/GPR39 modulates insulin receptor signaling, a major pathway in hepatic metabolism. Associated with the impaired signaling, ZnR/GPR39 KO livers exhibited increased tissue fibrosis, manifested by marked elevation of collagen expression, compared to wildtype (WT). Additionally, we found alteration of hepatocyte junctional proteins that was accompanied by increased macrophage infiltration and higher liver inflammation in ZnR/GPR39 KO mice. To determine the role of ZnR/GPR39 in ALI, we applied a mild LPS challenge that induced profound decrease in hepatic OCR, also leading to higher ROS generation in ZnR/GPR39 KO hepatocytes, but not in WT. We further found increased serum IL-2 and AST/ALT ratio only in ZnR/GPR39 KO mice. Our findings reveal a role of ZnR/GPR39 in controlling hepatic insulin receptor signaling and mitigating liver fibrosis and inflammation, thus underscoring the important role of ZnR/GPR39 in liver signaling and function.

Keywords:  Hepatic inflammation; Insulin receptor; Macrophage infiltration; Mitochondrial dysfunction; Tight junctions; Zinc; ZnR/GPR39

DOI:  https://doi.org/10.1016/j.redox.2024.103403
Diabetes. 2024 Nov 07. pii: db240388. [Epub ahead of print]

The effect of small increases in blood glucose on insulin secretion and endogenous glucose production in humans.

Clinton R Bruce, Teddy Ang, Jason D Toms, Giang M Dao, Jean Liu, Glenn M Ward, David N O'Neal, Dale J Morrison, Greg M Kowalski.

Small glycemic increments (≤0.5 mmol/L) can exert suppressive actions on endogenous glucose production (EGP) however it is unclear if this is an insulin dependent or independent process. Here, we performed a low-rate glucose infusion in control participants without diabetes and in people with type 1 diabetes (T1D) to better understand this phenomenon. Glucose kinetics, hormones and metabolites were measured during a 1 mg/kg/min glucose infusion (90 min) which rapidly increased glucose by ∼0.3 mmol/L in control participants. Insulin concentrations and secretion quickly increased by ∼20%, resulting in a ∼40% suppression of EGP, while glucose disposal remained unchanged. Free fatty acids (FFA) and glucagon were gradually suppressed to ∼30% below baseline at 60 min. When repeated under constant basal insulin concentrations in participants with T1D, glucose infusion caused only partial and transient EGP suppression, hence glucose increased in a near-linear manner, reaching levels ∼2 mmol/L above baseline at 90 min. FFAs and glucagon remained unchanged, while glucose disposal modestly increased. This demonstrates that small glycemic increments exert subtle stimulatory effects on insulin secretion that have potent metabolic actions on the liver and adipose tissue. It is conceivable that subtle increases in glucose could potentially serve as a signal for β-cell adaptation.

DOI: https://doi.org/10.2337/db24-0388
FASEB Bioadv. 2024 Nov;6(11): 526-538

Medium-chain fatty acid receptor GPR84 deficiency leads to metabolic homeostasis dysfunction in mice fed high-fat diet.

Akari Nishida, Ryuji Ohue-Kitano, Yuki Masujima, Hazuki Nonaka, Miki Igarashi, Takako Ikeda, Ikuo Kimura.

  Overconsumption of food, especially dietary fat, leads to metabolic disorders such as obesity and type 2 diabetes. Long-chain fatty acids, such as palmitoleate are recognized as the risk factors for these disorders owing to their high-energy content and lipotoxicity. In contrast, medium-chain fatty acids (MCFAs) metabolic benefits; however, their underlying molecular mechanisms remain unclear. GPR84 is an MCFA receptor, particularly for C10:0. Although evidence from in vitro experiments and oral administration of C10:0 in mice suggests that GPR84 is related to the metabolic benefits of MCFAs via glucose metabolism, its precise roles in vivo remain unclear. Therefore, the present study investigated whether GPR84 affects glucose metabolism and metabolic function using Gpr84-deficient mice. Although Gpr84-deficient mice were lean and had increased endogenous MCFAs under high-fat diet feeding conditions, they exhibited hyperglycemia and hyperlipidemia along with lower plasma insulin and glucagon-like peptide-1 (GLP-1) levels compared with wild-type mice. Medium-chain triglyceride (C10:0) intake suppressed obesity, and improved plasma glucose and lipid levels, and increased plasma GLP-1 levels in wild-type mice; however, these effects were partially attenuated in Gpr84-deficient mice. Our results indicate that long-term MCFA-mediated GPR84 activation improves the dysfunction of glucose and lipid homeostasis. Our findings may be instrumental for future studies on drug development with GPR84 as a potential target, thereby offering new avenues for the treatment of metabolic disorders like obesity and type 2 diabetes.

Keywords:  GPR84; decanoates; fatty acids; high‐fat diet; obesity; type 2 diabetes

DOI:  https://doi.org/10.1096/fba.2024-00075