CX3CL1 action on microglia protects from diet-induced obesity by restoring POMC neuronal excitability and melanocortin system activity impaired by high-fat diet feeding

Objective: Diet-induced obesity (DIO) is associated with hypothalamic microglial activation and dysfunction of the melanocortin pathway, but the molecular mechanisms linking the two remain unclear. Previous studies have hypothesized that microglial inflammatory signaling is linked with impaired pro-opiomelanocortin (POMC) neuron function, but this mechanism has never been directly tested in vivo. We addressed this hypothesis using the specific microglial silencing molecule, CX3CL1 (fractalkine), to determine whether reducing hypothalamic microglial activation can restore POMC/melanocortin signaling in the brain to protect against DIO. Methods: We performed metabolic analyses in mice with targeted viral overexpression of CX3CL1 in the hypothalamus exposed to high fat diet (HFD). Electrophysiologic recording in hypothalamic slices from POMC-MAPT-GFP mice was used to determine the effects of HFD feeding and microglial silencing via minocycline or CX3CL1 on GFP-labeled POMC neurons. Finally, mice with hypothalamic overexpression of CX3CL1 received central treatment with the melanocortin receptor antagonist SHU-9119 to determine whether melanocortin signaling is required for the metabolic benefits of CX3CL1. Results: We found that targeted expression of both soluble and membrane-bound forms of CX3CL1 in the mediobasal hypothalamus potently reduced weight gain and increased leptin sensitivity in animals exposed to high fat diet. The protective effect of CX3CL1 rescued diet-induced changes in POMC neuron excitability and required intact melanocortin receptor signaling in vivo. Conclusion: Our results provide the first evidence that HFD-induced POMC neuron dysfunction involves microglial activation. Furthermore, our study suggests that the anti-obesity action of CX3CL1 is mediated through the restoration of POMC neuron excitability and melanocortin signaling.

NTS Prlh overcomes orexigenic stimuli and ameliorates dietary and genetic forms of obesity

Calcitonin receptor (Calcr)-expressing neurons of the nucleus tractus solitarius (NTS; CalcrNTS cells) contribute to the long-term control of food intake and body weight. Here, we show that Prlh-expressing NTS (PrlhNTS) neurons represent a subset of CalcrNTS cells and that Prlh expression in these cells restrains body weight gain in the face of high fat diet challenge in mice. To understand the relationship of PrlhNTS cells to hypothalamic feeding circuits, we determined the ability of PrlhNTS-mediated signals to overcome enforced activation of AgRP neurons. We found that PrlhNTS neuron activation and Prlh overexpression in PrlhNTS cells abrogates AgRP neuron-driven hyperphagia and ameliorates the obesity of mice deficient in melanocortin signaling or leptin. Thus, enhancing Prlh-mediated neurotransmission from the NTS dampens hypothalamically-driven hyperphagia and obesity, demonstrating that NTS-mediated signals can override the effects of orexigenic hypothalamic signals on long-term energy balance.

Retraction Note: The melanocortin signaling cAMP axis accelerates repair and reduces mutagenesis of platinum-induced DNA damage

Editor's Note: this Article has been retracted; the Retraction Note is available at https://doi.org/10.1038/s41598-020-80467-y.

Melanocortin Pathways: Suppressed and Stimulated Melanocortin-4 Receptor (MC4R)

Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved.

Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.

Pharmacological treatment strategies for patients with monogenic obesity

The leptin melanocortin signaling pathway is playing a pivotal role for body weight regulation. Genetic defects within this cascade are leading to severe hyperphagia and early onset obesity. In most cases, due to persistent hyperphagia the affected patients are not able to stabilize body weight for a longer period of time with conservative treatment strategies based on lifestyle interventions. Therefore, it is of importance to implement alternative treatment options for these patients. This review provides an overview about the published pharmacological treatment attempts in respect to monogenic forms of obesity and summarizes recent research progress about the role of MC4R signaling and POMC derivatives for body weight regulation.