Biology subjects

Clemmensen, C.

Publications and source records attributed to Clemmensen, C..

9 recordsLinked to original sources

bioRxiv2026

A uniquely leptin sensitive hypothalamic neuron population limits hyperphagia and weight gain in diet-induced obesity

Despite widespread loss of leptin responsiveness in obesity, endogenous leptin continues to restrain feeding, yet the neural substrates that remain sensitive and mediate this effect are unknown. Combining spatial transcriptomics with single-nucleus RNA sequencing in mice with diet-induced obesity (DIO), we show that while most hypothalamic leptin receptor (Lepr) neurons minimally respond to elevated leptin, a single population defined by glucagon-like peptide-1 receptor (Glp1r) co-expression retains robust leptin sensitivity. These Lepr/Glp1r neurons project onto and restrain orexigenic Agrp neurons. Lepr deletion from Lepr/Glp1r neurons blocks the anorectic effect of exogenous leptin, reinstates hyperphagic responses normally suppressed in DIO, amplifies the obesogenic response to palatable diet, and unexpectedly attenuates hypothalamic microglial activation- a hallmark of DIO previously attributed to diet rather than leptin signaling. Hence, preserved leptin action through a single neuronal population governs downstream circuit activity to limit hyperphagia and weight gain during obesity.

molecular biology↗

bioRxiv2025

Genetic and preclinical evidence implicating chondroitin sulfate as a matritherapeutic target for the treatment of type 2 diabetes

Peptide-based treatments for type 2 diabetes (T2D) are often limited by variable patient responses, frequent discontinuation, and substantial costs. Emerging lines of evidence link the extracellular matrix (ECM) to the pathophysiology of T2D, highlighting a largely unexplored modality for managing this heterogenous disease. Chondroitin sulfate (CS), a major glycosaminoglycan in the ECM, has been suggested to improve cardiometabolic health in preclinical research. However, the human genetic and pharmacological basis for CS as an anti-diabetic target is largely unexplored. Here, we uncover novel and robust links between 12 CS-related genes and both glycemic traits and the risk of T2D in hu-mans. Complementing this, administration of CS leads to a profound lowering of blood glucose levels in severely diabetic mice and improves glucose tolerance and cardiac clearance of circulating glucose in diet-induced obese mice without causing hypoglyce-mia or other adverse effects. The improvement in glycemic control is accompanied by increased glucose-stimulated insulin secretion and enhanced insulin action, effects which seem to occur independent of the incretin system. The combination of human genetic evidence and appealing pharmacodynamic features highlights CS as a promising ECM-target for developing novel pharmacotherapies that complement current treatments for T2D.

physiology↗

bioRxiv2025

Nutritional hyperketonemia by dietary medium-chain fatty acids is driven by the liver without contribution from the intestine

Saturated medium-chain fatty acids (MCFAs) are ketogenic nutrients, and their dietary intake has been linked to health benefits such as improved energy balance and increased insulin sensitivity. Here, we tested the hypothesis that MCFA-mediated hyperketonemia is required for these benefits. Using tissue-specific 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) knockout mouse models, we show that the hyperketonemia induced by oral administration of triacylglycerols with the MCFA octanoic acid (C8:0-MCT) is mediated by hepatic, but not intestinal, ketogenesis. Remarkably, acute reductions in food intake and body weight induced by C8:0-MCT in obese mice were independent of hepatic ketogenesis; likewise, chronic protection against weight gain and marked improvements in insulin sensitivity elicited by MCFA-rich diets did not require hepatic ketogenesis. These data demonstrate that dietary MCFAs are potent bioactive lipids capable of inducing metabolic benefits independently of their ketogenic properties.

physiology↗

bioRxiv2025

Sex-specific metabolic responses to modulation of the glucagon-FGF21 axis in female mice

Fibroblast growth factor 21 (FGF21) and glucagon are key regulators of energy homeostasis. However, male-biased preclinical studies overlook critical sex differences in metabolism, hindering our understanding of FGF21s role in glucagons effects on females and effective treatments for women with metabolic diseases. We investigated the physiological effects of FGF21 deficiency in female mice fed a chow or obesogenic diet. During chow-feeding, FGF21 deficiency had minimal impact on body weight, response to fasting, and voluntary exercise. However, Fgf21 knockouts (KO) fed the obesogenic diet exhibited increased adiposity compared to wild-type females. Long-acting glucagon analog treatment (LA-Gcg) reduced body weight in both genotypes but exacerbated glucose intolerance in female KOs. We also compared the effects of LA-Gcg and semaglutide, a glucagon-like peptide 1 analog, in diet-induced obese males and females. LA-Gcg treatment induced greater weight loss and reduced food intake in males, whereas semaglutide had similar effects across sexes. Furthermore, glucose tolerance was significantly worse in LA-Gcg- treated females compared to males. Concluding, FGF21 deficiency potentiates diet-induced obesity in female mice, and LA-Gcg elicits sex-specific effects on body weight and glucose tolerance, highlighting potential sexual dimorphisms to glucagon-based therapies and underscoring the importance of considering sex as a biological variable in metabolic research. HighlightsO_LIBiological sex fundamentally affects metabolism, yet this variable remains largely underexplored in metabolic research. C_LIO_LIThis study investigates how FGF21 deficiency affects metabolic responses in female mice, and compares the effects of a glucagon analog (LA-Gcg) and semaglutide in both sexes. C_LIO_LIFGF21 deficiency exacerbates diet-induced obesity in female mice. LA-Gcgs effects on body weight and glucose tolerance are modulated by FGF21 and sex-dependent, with females showing a blunted response to weight loss and worse glucose tolerance. C_LIO_LIOur findings highlight sex-specific differences in metabolic responses, emphasizing the need to consider sex as a key variable in the development of glucagon-based therapies. C_LI

physiology↗

bioRxiv2024

A hypothalamus-brainstem circuit governs the prioritization of safety over essential needs

Animals continously adapt their behavior to balance survival and fulfilling essential needs. This balancing act involves prioritization of safety over the pursuit of other needs. However, the specific deep brain circuits that regulate safety-seeking behaviors in conjuction with motor circuits remain poorly understood. Here we identify a class of glutamatergic neurons in the lateral hypothalamic area (LHA) that target the midbrain locomotor-promoting pedunculopontine nucleus (PPN). Upon activation, this LHA-PPN pathway orchestrates context-dependent locomotion, prioritizing safety-directed movement over other essential needs such as foraging or mating. Remarkably, the neuronal activity of these circuits correlates directly with safety-seeking behavior. These circuits may respond to both intrinsic and external cues, playing a pivotal role in ensuring survival. Our findings uncover a circuit motif within the lateral hypothalamus that when recruited, prioritizes critical needs through the recruitment of an appropriate motor action.

neuroscience↗

bioRxiv2024

Overfeeding does not increase energy expenditure or energy excretion in mice

To curb the obesity epidemic, it is imperative that we improve our understanding of the mechanisms controlling fat mass and body weight regulation. While great progress has been made in mapping the biological feedback forces opposing weight loss, the mechanisms countering weight gain remain less well defined. Here, we integrate a mouse model of intragastric overfeeding with a comprehensive evaluation of the regulatory aspects of energy balance, encompassing food intake, energy expenditure, and fecal energy excretion. To evaluate the role of adipose tissue thermogenesis in the homeostatic protection against overfeeding-induced weight gain, we exposed uncoupling protein 1 (UCP1) knockout (KO) mice to overfeeding. Our results confirm that 7 days of 150% overfeeding induces [~]11% weight gain and triggers a potent and prolonged reduction in voluntary food intake that drives body weight back to baseline following overfeeding. Overfeeding has no effects on energy expenditure, consistent with the observation that mice lacking UCP1 are not compromised in their ability to defend against overfeeding-induced weight gain. These data emphasize that whole-body energy expenditure and adipose thermogenesis are not key contributors to protection against overfeeding in mice. Lastly, we show that fecal energy excretion decreases in response to overfeeding, primarily driven by a reduction in fecal output rather than in fecal caloric content. In conclusion, these results challenge the prevailing notion that adaptive thermogenesis contributes to the defense against weight gain induced by overfeeding. Instead, the protection against enforced weight gain in mice is primarily linked to a profound reduction in food intake.

physiology↗

bioRxiv2023

Cross-species comparison of pregnancy-induced GDF15

GDF15 (growth differentiation factor 15) is a stress-induced cytokine. Although the exact physiological function of GDF15 is not yet fully comprehended, the significant elevation of circulating GDF15 levels during gestation suggests a potential role for this hormone in pregnancy. This is corroborated by genetic association studies in which GDF15 and the GDF15 receptor, GDNF Family Receptor Alpha Like (GFRAL) have been linked to morning sickness and hyperemesis gravidarum (HG) in humans. Here, we studied GDF15 biology during pregnancy in mice, rats, macaques, and humans. In contrast to macaques and humans, mice and rats exhibited an underwhelming induction in plasma GDF15 levels in response to pregnancy ([~]75-fold increase in macaques vs. [~]2-fold increase in rodents). The changes in circulating GDF15 levels were corroborated by the magnitude of Gdf15 mRNA and GDF15 protein expression in placentae from mice, rats, and macaques. These species-specific findings may help guide future studies focusing on GDF15 in pregnancy and on the evaluation of pharmacological strategies to interfere with GDF15-GFRAL signaling to treat severe nausea and HG.

physiology↗

bioRxiv2022

The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance

Metformin is a blood glucose lowering medication with physiological effects that extend beyond its anti-diabetic indication. Recently, it was reported that metformin lowers body weight via induction of growth differentiation factor 15 (GDF15), which suppresses food intake by binding to the GDNF family receptor -like (GFRAL) in the hindbrain. At the same time, we demonstrated that recombinant GDF15 suppresses voluntary exercise in a GFRAL-dependent fashion. Here, we corroborate that metformin increases circulating GDF15 in mice and humans, but that it does not reduce voluntary running activity in mice. Unexpectedly, we fail to confirm previous reports that the GDF15-GFRAL pathway is necessary for the weight-lowering effects of metformin. Instead, our studies in wild-type, GDF15 knockout and GFRAL knockout mice suggest that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. The data presented here question whether metformin is a sufficiently strong stimulator of GDF15 to drive anorexia and weight loss and emphasize that additional work is needed to untangle the relationship among metformin, GDF15 and energy balance.

physiology↗

bioRxiv2020

Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor -like (GFRAL)-dependent mechanisms1,2. Conversely, the endogenous regulation and secretion of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent studies that prolonged, moderate- to high-intensity endurance exercise substantially increases circulating GDF15, in a time-dependent and reversible fashion, to peak levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice following forced treadmill running and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. Compared to other metabolic stressors, like fasting, acute high-fat diet feeding, severe caloric excess and temperature changes, exercise has a greater impact on circulating GDF15 levels. However, whereas pharmacological GDF15 inhibits appetite and suppresses wheel running activity via GFRAL, in response to exercise, the physiological induction of GDF15 does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. However, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for exercise aversion/fatigue. Thus, the physiological effects of GDF15 as an exerkine remain elusive.

physiology↗