Leptin Resistance and the Neuro-Adipose Connection

This article was submitted to Cellular Endocrinology, a section of the journal Frontiers in Endocrinology.Obesity is a public health concern affecting both genders at all ages around the world. The worldwide prevalence of obesity is rapidly increasing and has nearly doubled between 1980 and 2016. Consequently, it places a large financial burden on the economy due to the increased morbidity and mortality, as well as the reduced quality of life and development of chronic diseases. Obesity is typically characterized by excessive amounts of the hormone leptin, a cytokine-like molecule produced in white adipose tissue (WAT) that is secreted into the systemic circulation. The circulating levels of leptin are proportional to the amount of fat and function as the afferent signal in a negative feedback loop that seeks to maintain body fat in a very narrow range of variation. Leptin has a central role in body weight homeostasis due to its inhibition of food intake inhibition and stimulation of energy expenditure. The effect of leptin on body weight is attributed to its action in a specific brain region, the hypothalamus. Hence, leptin is released by adipocytes in proportion to the size of fat depots, enters the circulation, and reaches the central nervous system by crossing the blood-brain barrier (BBB) through receptor-mediated endocytosis in which it acts mainly through the arcuate nucleus of the hypothalamus to mediate most of its actions. Specifically, leptin modulates the activity of two types of neurons to inhibit appetite, through production of anorexigenic peptides by the pro-opiomelanocortin (POMC) neurons and suppression of the orexigenic agouti-related protein (AgRP) neurons. Besides acting on the hypothalamus to suppress appetite, leptin also induces lipolysis in WAT and thermogenesis in brown adipose tissue (BAT) and browning of WAT, via the activation of the sympathetic nervous system (SNS). However, in most obese subjects, despite its high serum levels, leptin fails to perform its physiological functions and consequently fails to reduce weight. This effect has been coined as leptin resistance.Fundação para Ciência e Tecnologia grants: (PD/BD/52437/2013, PTDC-BIM-MET-3750-2014); EMBO grant: (IG3077); Prémios Maratona Saúde 2015: (Diabetes); Human Frontiers Science Program grant:(RGY0070/2016).info:eu-repo/semantics/publishedVersio

A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages.

Conditional expression of diphtheria toxin receptor (DTR) is widely used for tissue-specific ablation of cells. However, diphtheria toxin (DT) crosses the blood-brain barrier, which limits its utility for ablating peripheral cells using Cre drivers that are also expressed in the central nervous system (CNS). Here we report the development of a brain-sparing DT, termed BRAINSPAReDT, for tissue-specific genetic ablation of cells outside the CNS. We prevent blood-brain barrier passage of DT through PEGylation, which polarizes the molecule and increases its size. We validate BRAINSPAReDT with regional genetic sympathectomy: BRAINSPAReDT ablates peripheral but not central catecholaminergic neurons, thus avoiding the Parkinson-like phenotype associated with full dopaminergic depletion. Regional sympathectomy compromises adipose tissue thermogenesis, and renders mice susceptible to obesity. We provide a proof of principle that BRAINSPAReDT can be used for Cre/DTR tissue-specific ablation outside the brain using CNS drivers, while consolidating the link between adiposity and the sympathetic nervous system

Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects.

Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theβ2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects

Brain-sparing sympathofacilitators mitigate obesity without adverse cardiovascular effects

Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theβ2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects

Corrigendum: A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages.

The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the following: [***Human Frontiers Science Program (HFSP) funds the labs of A.I.D. and P.C. ***]

Neuro-mesenchymal units control ILC2 and obesity via a brain–adipose circuit

Signals from sympathetic neurons and immune cells regulate adipocytes and thereby contribute to fat tissue biology. Interactions between the nervous and immune systems have recently emerged as important regulators of host defence and inflammation1,2,3,4. Nevertheless, it is unclear whether neuronal and immune cells co-operate in brain–body axes to orchestrate metabolism and obesity. Here we describe a neuro-mesenchymal unit that controls group 2 innate lymphoid cells (ILC2s), adipose tissue physiology, metabolism and obesity via a brain–adipose circuit. We found that sympathetic nerve terminals act on neighbouring adipose mesenchymal cells via the β2-adrenergic receptor to control the expression of glial-derived neurotrophic factor (GDNF) and the activity of ILC2s in gonadal fat. Accordingly, ILC2-autonomous manipulation of the GDNF receptor machinery led to alterations in ILC2 function, energy expenditure, insulin resistance and propensity to obesity. Retrograde tracing and chemical, surgical and chemogenetic manipulations identified a sympathetic aorticorenal circuit that modulates ILC2s in gonadal fat and connects to higher-order brain areas, including the paraventricular nucleus of the hypothalamus. Our results identify a neuro-mesenchymal unit that translates cues from long-range neuronal circuitry into adipose-resident ILC2 function, thereby shaping host metabolism and obesity