Biology subjects

Marcher, A.-B.

Publications and source records attributed to Marcher, A.-B..

3 recordsLinked to original sources

bioRxiv2025

Single Nucleus Multiome Analysis Reveals Early Inflammatory Response to High-Fat Diet in Mouse Pancreatic Islets

In periods of sustained hyper-nutrition, pancreatic {beta}-cells undergo functional compensation through transcriptional upregulation of gene programs driving insulin secretion. This adaptation is essential for maintaining systemic glucose homeostasis and metabolic health. Using single nuclei multiomics, we have mapped the early transcriptional compensation mechanisms in murine islets of Langerhans exposed to high-fat diet (HFD) for one and three weeks. We show that {beta}-cells exhibit the largest transcriptional response to HFD, characterized by early activation of proinflammatory eRegulons and downregulation of {beta}-cell identity genes, particularly in a distinct subset of {beta}-cells. Our observations translate to humans, as we observe an increase in the inflammatory gene signatures in human {beta}-cells in pre-diabetes and diabetes. Collectively, these observations point to cellular cross-talk through proinflammatory signaling as a central and early driver of {beta}-cell dysfunction that limits the compensatory capacity of {beta}-cells, which is closely linked to the development of diabetes.

cell biology↗

bioRxiv2020

The Epidermal Barrier is Indispensable for Systemic Energy Homeostasis

ObjectivesHomeostatic regulation of body temperature is fundamental to mammalian physiology and is controlled by acute and chronic responses of local, endocrine and neuronal regulators. Although the skin is the largest sensory organ of the human body, and plays a fundamental role in regulating body temperature, it is surprising that adaptive alterations in skin functions and morphology only vaguely have been associated with physiological responses to cold stress or sensation of ambient temperatures. MethodsTo unravel the physiological responses to a compromised epidermal barrier in detail we have used animal models with either defects in skin lipid metabolism (ACBP-/- and skin-specific ACBP-/- knockout mice) or defects in skin structural proteins (ma/ma Flgft/ft). The primary objective was to clarify how defects in epidermal barrier function affect 1) energy expenditure by indirect calorimetry, 2) response to high fat feeding and a high oral glucose load and 3) expression of brown-selective gene programs by quantitative PCR in inguinal WAT (iWAT). ResultsWe show that mice with a compromised epidermal barrier function exhibit increased energy expenditure, increased food intake, browning of the iWAT, and resistance to diet-induced obesity. The metabolic phenotype, including browning of the iWAT, is reversed by housing the mice at thermoneutrality (30{degrees}C) or by pharmacological {beta}-adrenergic blocking. These findings show that a compromised epidermal barrier induces a {beta}-adrenergic response that increases energy expenditure and browning of the white adipose tissue to maintain a normal body temperature. ConclusionOur findings show that the epidermal barrier plays a key role in maintaining systemic metabolic homeostasis. HighlightsEnergy expenditure is significantly augmented in mice with impaired epidermal barrier. Mice with compromised barrier display increased food intake while maintaining normal bodyweight. Mice with an impaired epidermal barrier are resistant to diet-induced obesity and insulin resistance. Compromised barrier function induces expression of brown-selective gene programs in iWAT. Thermoneutral housing or blocking {beta}-adrenergic signaling prevents induction of brite-selective genes in iWAT and reverses food intake.

biochemistry↗

bioRxiv2020

The gliopeptide ODN, a ligand for the benzodiazepine site of GABAA receptors, boosts functional recovery after stroke

Following stroke, the survival of neurons and their ability to re-establish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABAA receptors (GABAAR). Conversely, in the late phase, negative allosteric modulation of GABAAR can correct the sub-optimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABAAR synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which make it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in two different paradigms of experimental stroke in mice. Furthermore, we bring evidence that during the sub-acute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity. SIGNIFICANCE STATEMENTStroke remains a devastating clinical challenge because there is no efficient therapy to either minimize neuronal death with neuroprotective drugs or to enhance spontaneous recovery with neurorepair drugs. Around the brain damage, the peri-infarct cortex can be viewed as a reservoir of plasticity. However, the potential of wiring new circuits in these areas is restrained by a chronic excess of GABAergic inhibition. Here we show that an astrocyte-derived peptide (ODN), can be used as a delayed treatment, to safely correct cortical excitability and facilitate sensorimotor recovery after stroke.

neuroscience↗