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Hypothalamus-adipose tissue crosstalk: neuropeptide Y and the regulation of energy metabolism

Abstract (provisional)

Neuropeptide Y (NPY) is an orexigenic neuropeptide that plays a role in regulating adiposity by promoting energy storage in white adipose tissue and inhibiting brown adipose tissue activation in mammals. This review describes mechanisms underlying NPY's effects on adipose tissue energy metabolism, with an emphasis on cellular proliferation, adipogenesis, lipid deposition, and lipolysis in white adipose tissue, and brown fat activation and thermogenesis. In general, NPY promotes adipocyte differentiation and lipid accumulation, leading to energy storage in adipose tissue, with effects mediated mainly through NPY receptor sub-types 1 and 2. This review highlights hypothalamus-sympathetic nervous system-adipose tissue innervation and adipose tissue-hypothalamus feedback loops as pathways underlying these effects. Potential sources of NPY that mediate adipose effects include the bloodstream, sympathetic nerve terminals that innervate the adipose tissue, as well as adipose tissue-derived cells. Understanding the role of central vs. peripherally-derived NPY in whole-body energy balance could shed light on mechanisms underlying the pathogenesis of obesity. This information may provide some insight into searching for alternative therapeutic strategies for the treatment of obesity and associated diseases.

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Alex’s Notes: The purpose of this review is to provide an in-depth look at neuropeptide Y (NPY) and how it mediates energy regulation between the hypothalamus and our adipose tissue. It is truly a fascinating area of research with much theoretical potential for managing obesity and related fat-induced problems. There is a reason I used the phrase “theoretical potential” in the last sentence. Energy homeostasis is governed by a complex neuroendocrine system referred to as the hypothalamus-adipose tissue axis in this review. It includes appetite regulatory hypothalamic peptides, as well as adipocyte-derived peripheral signals such as leptin that work to integrate information about energy status.

In the brain, NPY is concentrated within the hypothalamus, brain stem, and anterior pituitary. Given that the hypothalamus is the boss of metabolism and the anterior pituitary secretes various hormones to regulate metabolism, there is already a clear connection between NPY and energy status. NPY neurons sense and integrate energy signals from the body about nutrient status (blood glucose levels, ghrelin, leptin, insulin, etc.) and release NPY in response to energy deficit or increased metabolic demand (exercise, cold, pregnancy, etc.). This affects food intake by working with other regulatory factors of the brain, but more importantly, it regulates energy utilization in adipose tissue via various NPY receptors.

The main receptors are NPYR1, NPYR2, and NPYR5. NPYR1 is directly involved in energy intake and expenditure, while NPYR2 and NPYR5 regulate food intake and energy expenditure by modulating NPY release. Outside of brain, NPY is present mainly in sympathetic nerves and white adipose tissue. Interestingly, it appears to be deposited after the fact, since preadipocytes (immature fat cells) do not contain NPY. Regardless, expression of NPY within adipose tissue is a common feature of obesity in numerous animal models.

In short, NPY has hyperplasic, adipogenic, and antilipolytic effects, mediated primarily through NPYR2. This means it stimulates the creation and growth of fat cells while inhibiting their breakdown. This is best demonstrated in a rodent study where genetic modification removed the NPYR2 receptor from the bodily tissues (fat included) which prevented diet-induced obesity and significantly increased energy expenditure and physical activity. Moreover, the same type of mice fed a normal diet showed no effect on food intake or weight, suggesting that NPYR2 plays an important role in the regulation of fuel selection and physical activity. Importantly, neither muscle nor bone mass was affected, providing further support to the therapeutic potential of NPY-based drugs in the treatment of obesity.

Effects on NPY on actually fat oxidation occur chiefly through NPYR1, with the exact effects being influenced by nutritional status, genetics, and other cellular factors. As mentioned, NPY is present in sympathetic nerves, and this can potentially affect fat metabolism due to being co-released with adrenaline and noradrenaline in different quantities depending on stimulation intensity and the pattern of activation. Sympathetic nervous output acts mainly upon beta-adrenergic receptors to simulate the breakdown and oxidation of fat tissue. However, NPY secreted from sympathetic neurons inhibit beta-adrenergic-mediated fat oxidation.

It must now be emphasized how all this comes together. The NPY system represents a form of communication between the hypothalamus and adipose tissue. The hypothalamus is the energy sensory center for signals produced by bodily tissues such as the intestines and fat tissue. Adipose tissue releases numerous adipokines such as adiponectin, apelin, resistin, and leptin that inform the brain of changes in body fat mass so that the brain may mount an adaptive response that adjusts energy intake and metabolism to stabilize fat stores in the long term. The majority of NPY is secreted by the neurons of the brain and works to increase energy intake, storage, and reduce energy expenditure.

Clinical studies have demonstrated circulating NPY to be elevated in obese women compared to a control group, and it has also been shown to be elevated in genetically obese mice. Having a complete understanding of NPY in energy homeostasis has vast implications for weight-loss and for controlling the development and treatment of obesity. However, as the authors of this review conclude,

“Whether NPY can be used as a biomarker for obesity awaits further determination. A body of studies aimed to manipulate NPY and NPY receptor-subtype function highlight the feasibility of targeting the NPY system for therapeutic strategies. However, the mechanisms underlying the effects of NPY are complicated, especially in view of brain-adipose cross talk.”

I for one look forward to seeing what becomes of future research.

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