Biology subjects

Giroud, M.

Publications and source records attributed to Giroud, M..

4 recordsLinked to original sources

bioRxiv2025

The obesity-linked peptide SP16 regulates adipocytes through GIP and insulin receptor

Obesity has emerged as a global epidemic and represents a major public health concern due to its profound implications for metabolic diseases. While recent pharmacological interventions primarily aim to reduce food intake, enhancing energy expenditure in adipose tissue offers a promising complementary approach. In this study, we identify that SP16, a synthetic 1- antitrypsin derived peptide, is a novel GIP (gastric inhibitory peptide) receptor agonist. SP16 promotes lipolysis via the cAMP pathway, resulting in increased mitochondrial oxygen consumption in adipocytes. Furthermore, SP16 binds to the insulin receptor, and at high concentrations, it attenuates insulin receptor signaling. In diet-induced obese (DIO) mice, acute SP16 treatment improved glucose clearance, elevated circulating free fatty acids, and decreased leptin levels. Ex vivo analyses of epididymal white adipose tissue corroborated these findings, demonstrating enhanced lipolysis in SP16-treated mice. In conclusion, SP16 emerges as a novel lipolytic peptide with beneficial metabolic effects. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/660082v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@135f172org.highwire.dtl.DTLVardef@7e8152org.highwire.dtl.DTLVardef@15c6937org.highwire.dtl.DTLVardef@1ffc295_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with Biorender.com

pharmacology and toxicology↗

bioRxiv2025

SARM1 base-exchange inhibitors induce SARM1 activation and neurodegeneration at low doses

SARM1 has emerged as a promising therapeutic target in neurology due to its central role in axonal degeneration and its amenability to different modes of small molecule inhibition. One chemical approach to modulate SARM1 involves orthosteric inhibition via a SARM1-mediated base-exchange reaction between a small molecule and nicotinamide adenine dinucleotide (NAD+), the substrate of SARM1, to generate the active inhibitor. Here, we report that subinhibitory concentrations of SARM1 base-exchange inhibitors (BEIs) paradoxically increase SARM1 activity and worsen SARM1-induced cell death and neuronal damage in vitro. Low dose administration of RO-7529, a SARM1 BEI, exacerbated experimental autoimmune encephalomyelitis (EAE)-induced neurodegeneration in vivo. Our data highlight a unique pharmacological feature of SARM1 BEIs that may limit their therapeutic application in disorders associated with SARM1 activation and axonal degeneration.

neuroscience↗

bioRxiv2021

The obesity-linked human lncRNA AATBC regulates adipocyte plasticity by stimulating mitochondrial dynamics and respiration

Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, the activation of thermogenic brown and beige adipocytes is linked to improved cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this adipocyte plasticity could help improving energy balance and weight loss. Here, we show that the long non-coding RNA (lncRNA) Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Searching for new human lncRNAs implicated in adipocyte biology we compared transcriptional profiles of human adipose tissues and cultured adipocytes and discovered that AATBC was enriched in thermogenic conditions. Using primary human adipocytes and immortalized human adipocytes we found that gain-of-function of AATBC enhanced the thermogenic phenotype whereas loss-of-function diminished this effect. The AATBC-mediated increase in mitochondrial respiration was linked to a more fragmented mitochondrial network and vice versa. While we found that AATBC is predominantly located in the nucleus, its effect on global transcription was only marginal. As AATBC is specific to humans, we expressed AATBC in adipose tissue of mice to study its systemic impact, which led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, body mass index and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.

molecular biology↗

bioRxiv2020

HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signaling

Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we show that Heart- and neural crest derivatives-expressed protein 2 (HAND2) is an obesity-linked adipocyte transcription factor regulated by glucocorticoids and required for adipocyte differentiation in vitro. In a large cohort of humans with obesity, white adipose tissue (WAT) HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes, induced early in differentiation and responded to dexamethasone, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in human multipotent adipose-derived stem cells (hMADS) or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Using a combinatorial RNAseq approach we identified gene clusters regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.

molecular biology↗