Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease

Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning

Obesity-related diseases such as diabetes and dyslipidemia result from metabolic alterations including the defective conversion, storage and utilization of nutrients, but the central mechanisms that regulate this process of nutrient partitioning remain elusive. As positive regulators of feeding behaviour, agouti-related protein (AgRP) producing neurons are indispensible for the hypothalamic integration of energy balance. Here, we demonstrate a role for AgRP-neurons in the control of nutrient partitioning. We report that ablation of AgRP-neurons leads to a change in autonomic output onto liver, muscle and pancreas affecting the relative balance between lipids and carbohydrates metabolism. As a consequence, mice lacking AgRP-neurons become obese and hyperinsulinemic on regular chow but display reduced body weight gain and paradoxical improvement in glucose tolerance on high-fat diet. These results provide a direct demonstration of a role for AgRP-neurons in the coordination of efferent organ activity and nutrient partitioning, providing a mechanistic link between obesity and obesity-related disorders

Hypothalamic regulation of energy balance: a key role for DICER miRNA processing in arcuate POMC neurons

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Central lipid detection and the regulation of feeding behavior

The modern abundance of energy-rich foods combined with a shift to more sedentary lifestyles has led to a thermodynamic imbalance in which excessive caloric intake and reduced energy expenditure account for the prevalence of obesity. In particular, exposure to lipid-rich diet is thought to promote metabolic alteration in peripheral tissue associated with obesity-related diseases. The regulation of energy balance depends on the ability of the brain to provide an adaptive response to change in circulating factors of hunger and satiety. The hypothalamus is particularly regarded as key integrative structure but, aside from hypothalamic-mediated homeostatic control, feeding behavior is also modulated by sensory inputs, such as tastes and odors, as well as by affective or emotional states. The reinforcing and motivational aspects of food are closely tied to the release of the neurotransmitter dopamine by the mesolimbic system, which is stimulated by calorie-dense foods as well as by most other objects of desire. Therefore feeding behavior is regulated by homeostatic as well as non-homeostatic inputs from the hypothalamus and the mesolimbic region. Interestingly, these structures expresses several enzymes involved in the processing of triglyceride and fatty acid and the recent literature provide growing evidence that fatty acid metabolism within discrete brain regions can function as sensor of nutrient availability directly control the hedonic and the homeostatic aspect of feeding

Central lipid detection and the regulation of feeding behavior

The modern abundance of energy-rich foods combined with a shift to more sedentary lifestyles has led to a thermodynamic imbalance in which excessive caloric intake and reduced energy expenditure account for the prevalence of obesity. In particular, exposure to lipid-rich diet is thought to promote metabolic alteration in peripheral tissue associated with obesity-related diseases. The regulation of energy balance depends on the ability of the brain to provide an adaptive response to change in circulating factors of hunger and satiety. The hypothalamus is particularly regarded as key integrative structure but, aside from hypothalamic-mediated homeostatic control, feeding behavior is also modulated by sensory inputs, such as tastes and odors, as well as by affective or emotional states. The reinforcing and motivational aspects of food are closely tied to the release of the neurotransmitter dopamine by the mesolimbic system, which is stimulated by calorie-dense foods as well as by most other objects of desire. Therefore feeding behavior is regulated by homeostatic as well as non-homeostatic inputs from the hypothalamus and the mesolimbic region. Interestingly, these structures expresses several enzymes involved in the processing of triglyceride and fatty acid and the recent literature provide growing evidence that fatty acid metabolism within discrete brain regions can function as sensor of nutrient availability directly control the hedonic and the homeostatic aspect of feeding

Utilization of a Clark electrode device as a respirometer for small insects: A convincing test on ants allowing to detect discontinuous gas exchange

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Rôle de la détection centrale des lipides dans le contrôle nerveux de la balance énergétique

Il existe, dans l’hypothalamus et dans d’autres structures cérébrales comme l’hippocampe ou le striatum, des neurones spécialisés capables de détecter les variations quotidiennes des acides gras circulants. Ces neurones participent au maintien à l’équilibre de la balance énergétique en contrôlant la prise alimentaire, la sécrétion d’insuline ou la production hépatique de glucose. Les mécanismes moléculaires relayant l’effet des acides gras impliquent des récepteurs d’acides gras comme FAT (fatty acid transporter)/CD36. Toute dérégulation de cette détection centrale des acides gras peut contribuer à la mise en place des maladies métaboliques, telles que l’obésité ou le diabète de type 2

Ageing as a Two-Phase Process: Development of a new Theoretical Framework

International audienceHuman ageing, along with the ageing of conventional model organisms, is frequently depicted as a continuous and progressive decline of biological capabilities. Additionally, it is assumed that the risk of mortality increases exponentially during this process. However, it is pivotal to acknowledge that not all organisms experience ageing identically and that our understanding of the phenomenon is coloured by human-centric views. Ageing is multifaceted and influences a diverse range of species in varying ways. For instance, certain organisms undergo swift declines post-reproduction, while others exhibit almost insubstantial changes throughout their existence. This vast array renders the classification of universally applicable "ageing attributes" a daunting task. It is nonetheless essential to also recognize that not all ageing features are organism-specific. The existence of these common attributes has paved the way for identifying the "hallmarks of ageing". These hallmarks are processes that are intertwined with age, amplified during accelerated ageing, and manipulations of which can potentially modulate or even reverse the ageing process. Yet, a glaring observation is that individuals within a single population age at varying rates.. To address this variation, demographers have coined the term 'frailty'. Concurrently, scientific advancements have ushered in the era of molecular clocks. These innovations enable a distinction between an individual's chronological age (time since birth) and biological age (physiological status and corresponding mortality risk). Rera and colleagues, in 2011, unveiled the "Smurf" phenotype in Drosophila, delineating an age-linked escalation in intestinal permeability that presages imminent mortality. This phenotype not only acts as a predictor of natural death but also identifies individuals exhibiting heightened inflammation, energy-store depletion, and compromised motility, among other age-induced traits. Subsequent studies have revealed the Smurf phenotype's presence in organisms like nematodes, zebrafish, and mice, invariably acting as a death precursor. A compelling study by Zane et al. demonstrated that the transcriptional hallmarks of ageing predominantly impact Smurf individuals, with time primarily influencing transcriptional irregularities. Collectively, these findings have steered our conception of ageing towards a framework where ageing is not a linear and continuous progression. Instead, a lifespan is marked by two distinct, necessary phases, discernible in vivo across diverse organisms, courtesy of the Smurf phenotype. This framework additionally includes a mathematical enunciation of longevity trends based on three experimentally measurable parameters, coupled with an analysis of the transcriptome in flies, contingent on both their chronological and biological ages. Moreover, it facilitates a fresh perspective on the evolution of ageing as a function. In this present article, we aim to delineate and explore the foundational principles of this innovative framework, emphasising its potential to reshape our understanding of ageing, challenge its conventional definitions, and recalibrate our comprehension of its evolutionary trajectory

Two phases model of ageing in mice: towards a better identification of age-related and late-life metabolic decline [Registered Report Stage 1 Protocol]

Abstract: Since being described in Drosophila melanogaster in 2011, the Smurf phenotype, has been seen to be evolutionarily conserved in nematode and zebrafish, and has helped to identify the discontinuous nature of ageing and predict impending death from natural causes as well as from environmental stresses. This phenotype allowed us to model ageing as being made of two successive phases : a phase A where individuals are healthy and have no risk of mortality but an age-dependent increasing risk of entering phase B, followed by a phase B where individuals show the so-called hallmarks of ageing and a high risk of death. We will test here whether these two consecutive phases of ageing separated by the Smurf transition are a conserved feature of ageing in the classical mammalian laboratory model Mus musculus. Thanks to a longitudinal longevity study using both males and females from two different mouse genetic backgrounds and by integrating physiological, metabolic and molecular measurements with the life history of approximately 150 mice, we are attempting to identify a phenotypic signature typical of the last phase of life, observable at any chronological age. Validating the two-phase ageing model in a mammalian organism would allow the high risk of imminent death to be better characterized in this model and would extend its implications to a broader range of species for aging research. </p

Laforin, a dual specificity phosphatase involved in Lafora disease, regulates insulin response and whole-body energy balance in mice

International audienceLaforin is a dual specificity protein phosphatase involved in Lafora disease (LD), a fatal form of progressive myoclonus epilepsy characterized by neurodegeneration and the presence of intracellular polyglucosan inclusions (Lafora bodies) in different tissues. In this work, we describe that mice lacking laforin (epm2a-/-) have enhanced insulin response leading to altered whole-body energy balance. This enhanced insulin response overactivates the Akt pathway which increases glucose uptake in the heart, resulting in increased glycogen levels and the formation of polyglucosan inclusions. In addition, enhanced insulin response resulted in increased liver lipid biosynthesis, resulting in hepatic steatosis. On the contrary, overexpression in rat hepatoma FTO2B cells of native laforin but not of a form lacking phosphatase activity (C266S) resulted in attenuation of insulin signaling. These results define laforin as a new regulator of insulin sensitivity, which provides novel insights into LD pathogenesis and identifies this phosphatase as a potential novel component of the insulin signaling cascade