Recent CIG publications Archive


Cells.: co-auth.: W. Wahli

Cells. 2021 Dec 21;11(1):4. doi: 10.3390/cells11010004.

Adipose-Specific PPARα Knockout Mice Have Increased Lipogenesis by PASK-SREBP1 Signaling and a Polarity Shift to Inflammatory Macrophages in White Adipose Tissue

Terry D Hinds Jr 1 2 3Zachary A Kipp 1Mei Xu 1Frederique B Yiannikouris 1 2Andrew J Morris 4 5Donald F Stec 6Walter Wahli 7 8 9David E Stec 10


The nuclear receptor PPARα is associated with reducing adiposity, especially in the liver, where it transactivates genes for β-oxidation. Contrarily, the function of PPARα in extrahepatic tissues is less known. Therefore, we established the first adipose-specific PPARα knockout (PparaFatKO) mice to determine the signaling position of PPARα in adipose tissue expansion that occurs during the development of obesity. To assess the function of PPARα in adiposity, female and male mice were placed on a high-fat diet (HFD) or normal chow for 30 weeks. Only the male PparaFatKO animals had significantly more adiposity in the inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT) with HFD, compared to control littermates. No changes in adiposity were observed in female mice compared to control littermates. In the males, the loss of PPARα signaling in adipocytes caused significantly higher cholesterol esters, activation of the transcription factor sterol regulatory element-binding protein-1 (SREBP-1), and a shift in macrophage polarity from M2 to M1 macrophages. We found that the loss of adipocyte PPARα caused significantly higher expression of the Per-Arnt-Sim kinase (PASK), a kinase that activates SREBP-1. The hyperactivity of the PASK-SREBP-1 axis significantly increased the lipogenesis proteins fatty acid synthase (FAS) and stearoyl-Coenzyme A desaturase 1 (SCD1) and raised the expression of genes for cholesterol metabolism (Scarb1Abcg1, and Abca1). The loss of adipocyte PPARα increased Nos2 in the males, an M1 macrophage marker indicating that the population of macrophages had changed to proinflammatory. Our results demonstrate the first adipose-specific actions for PPARα in protecting against lipogenesis, inflammation, and cholesterol ester accumulation that leads to adipocyte tissue expansion in obesity.

Keywords: FAS; SCD1; adipocyte; adipogenesis; cholesterol esters; fatty acid synthase; inflammation; lipid signaling; obesity; sexual dimorphism.


J Diabetes Investig.: auth.: B.Thorens

J Diabetes Investig. 2022 Jan 6. doi: 10.1111/jdi.13745. Online ahead of print.

Neuronal regulation of glucagon secretion and gluconeogenesis

Bernard Thorens 1


Hypoglycemia almost never develops in healthy individuals because multiple hypoglycemia sensing systems, located in the periphery and in the central nervous system trigger a coordinated counterregulatory hormonal response to restore normoglycemia. This involves not only the secretion of glucagon but also of epinephrine, norepinephrine, cortisol and growth hormone. Increased hepatic glucose production is also stimulated by direct autonomous nervous connections to the liver that stimulate glycogenolysis and gluconeogenesis. This counterregulatory response, however, becomes deregulated in a significant fraction of diabetic patients that receive insulin therapy. This leads to risk of developing hypoglycemic episodes, of increasing severity, which negatively impact the quality of life of the patients. How hypoglycemia is detected by the central nervous system is being actively investigated. Recent studies using novel molecular biological, optogenetic and chemogenetic techniques, allow the characterization of glucose sensing neurons, the mechanisms of hypoglycemia detection, the neuronal circuits in which they are integrated and the physiological responses they control. This review will discuss recent studies aimed at identifying central hypoglycemia sensing neuronal circuits, how neurons are activated by hypoglycemia, and how they restore normoglycemia.


Cancers: auth.: group Fajas

by Dorian V. Ziegler *Katharina Huber and Lluis Fajas *Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland*Authors to whom correspondence should be addressed. Academic Editor: Vanessa Soto-Cerrato Cancers 202214(1), 153; 17 November 2021 / Revised: 22 December 2021 / Accepted: 23 December 2021 / Published: 29 December 2021

Simple Summary 

Autophagy is an intracellular catabolic program regulated by multiple external and internal cues. A large amount of evidence unraveled that cell-cycle regulators are crucial in its control. This review highlights the interplay between cell-cycle regulators, including cyclin-dependent kinase inhibitors, cyclin-dependent kinases, and E2F factors, in the control of autophagy all along the cell cycle. Beyond the intimate link between cell cycle and autophagy, this review opens therapeutic perspectives in modulating together these two aspects to block cancer progression.


In the past decade, cell cycle regulators have extended their canonical role in cell cycle progression to the regulation of various cellular processes, including cellular metabolism. The regulation of metabolism is intimately connected with the function of autophagy, a catabolic process that promotes the efficient recycling of endogenous components from both extrinsic stress, e.g., nutrient deprivation, and intrinsic sub-lethal damage. Mediating cellular homeostasis and cytoprotection, autophagy is found to be dysregulated in numerous pathophysiological contexts, such as cancer. As an adaptative advantage, the upregulation of autophagy allows tumor cells to integrate stress signals, escaping multiple cell death mechanisms. Nevertheless, the precise role of autophagy during tumor development and progression remains highly context-dependent. Recently, multiple articles has suggested the importance of various cell cycle regulators in the modulation of autophagic processes. Here, we review the current clues indicating that cell-cycle regulators, including cyclin-dependent kinase inhibitors (CKIs), cyclin-dependent kinases (CDKs), and E2F transcription factors, are intrinsically linked to the regulation of autophagy. As an increasing number of studies highlight the importance of autophagy in cancer progression, we finally evoke new perspectives in therapeutic avenues that may include both cell cycle inhibitors and autophagy modulators to synergize antitumor efficacy. View Full-TextKeywords: cell cycle regulatorsautophagyCKICDKsE2Fcancer


Front Neurosci.: auth.: group Croizier

Front Neurosci. 2021 Nov 30;15:748186. doi: 10.3389/fnins.2021.748186. eCollection 2021.

Ontogeny of the Projections From the Dorsomedial Division of the Anterior Bed Nucleus of the Stria Terminalis to Hypothalamic Nuclei

Marc Lanzillo 1Manon Gervais 1Sophie Croizier 1


The bed nucleus of the stria terminalis (BNST) is a telencephalic structure well-connected to hypothalamic regions known to control goal-oriented behaviors such as feeding. In particular, we showed that the dorsomedial division of the anterior BNST innervate neurons of the paraventricular (PVH), dorsomedial (DMH), and arcuate (ARH) hypothalamic nuclei as well as the lateral hypothalamic area (LHA). While the anatomy of these projections has been characterized in mice, their ontogeny has not been studied. In this study, we used the DiI-based tract tracing approach to study the development of BNST projections innervating several hypothalamic areas including the PVH, DMH, ARH, and LHA. These results indicate that projections from the dorsomedial division of the anterior BNST to hypothalamic nuclei are immature at birth and substantially reach the PVH, DMH, and the LHA at P10. In the ARH, only sparse fibers are observed at P10, but their density increased markedly between P12 and P14. Collectively, these findings provide new insight into the ontogeny of hypothalamic circuits, and highlight the importance of considering the developmental context as a direct modulator in their proper formation.

Keywords: ARH; DMH; DiI-based tract tracing; LHA; PVH; bed nuclei of the stria terminalis; ontogeny.


Eur J Hum Genet.: co-auth.: A. Reymond

Eur J Hum Genet. 2021 Dec 17. doi: 10.1038/s41431-021-01000-x. Online ahead of print.

The use of polygenic risk scores in pre-implantation genetic testing: an unproven, unethical practice

Francesca Forzano 1Olga Antonova 2Angus Clarke 3Guido de Wert 4Sabine Hentze 5Yalda Jamshidi 6Yves Moreau 7Markus Perola 8Inga Prokopenko 9 10 11Andrew Read 12Alexandre Reymond 13Vigdis Stefansdottir 14Carla van El 15Maurizio Genuardi 16 17Executive Committee of the European Society of Human GeneticsPublic and Professional Policy Committee of the European Society of Human Genetics


Elife.: auth.: group Franken

Elife. 2021 Dec 13;10:e69773. doi: 10.7554/eLife.69773. Online ahead of print.

The sleep-wake distribution contributes to the peripheral rhythms in PERIOD-2

Marieke Mb Hoekstra 1Maxime Jan 1Georgia Katsioudi 1Yann Emmenegger 1Paul Franken 1


In the mouse, Period-2 (Per2) expression in tissues peripheral to the suprachiasmatic nuclei (SCN) increases during sleep deprivation and at times of the day when animals are predominantly awake spontaneously, suggesting that the circadian sleep-wake distribution directly contributes to the daily rhythms in Per2. We found support for this hypothesis by recording sleep-wake state alongside PER2 bioluminescence in freely behaving mice, demonstrating that PER2 bioluminescence increases during spontaneous waking and decreases during sleep. The temporary reinstatement of PER2-bioluminescence rhythmicity in behaviorally arrhythmic SCN-lesioned mice submitted to daily recurring sleep deprivations substantiates our hypothesis. Mathematical modelling revealed that PER2 dynamics can be described by a damped harmonic oscillator driven by two forces: a sleep-wake-dependent force and a SCN-independent circadian force. Our work underscores the notion that in peripheral tissues the clock gene circuitry integrates sleep-wake information and could thereby contribute to behavioral adaptability to respond to homeostatic requirements.

Keywords: computational biology; mouse; neuroscience; systems biology.