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Author Topic: Relationships between adipose tissues and brain: what do we learn from studies ?  (Read 5088 times)

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To further my hypothesis that memory is represented in the fatty tissue of the white and grey matter (thus being both the origin and recipient of much neuronal activity).

I feel that this study supports my theory and some may find it interesting. As we well know, drugs can stop memories from ever being formed and/or allow for some suppressed memories to eventually allow for processing and healing, for example.

Memories, I assert, are "simply" layered and incrementally built structures of actions (or Motor Programs) from internal and external stimuli. It's all about doing stuff and that stuff is all about SURVIVAL with pleasure and happiness foremost in mind.

Relationships between adipose tissues and brain: what do we learn from animal studies?



Over the last decades, more and more data supporting the importance of the relationships between the brain and adipose tissues (white and brown) in regards of body weight regulation and energy homeostasis have been published. Indeed the brain via the autonomic nervous system participates to the regulation of different parameters such as the metabolic (lipolysis, lipogenesis and thermogeneis), and secretory (leptin and other adipokines) activities but also plasticity (proliferation differentiation and apoptosis) of adipose tissues.

In turn the various fat pads will send information via sensory innervation of white adipose tissue as well as metabolic and hormonal signals acting directly on some brain areas. Altogether these results showed the presence of a neural feedback loop between adipose tissues and the brain which plays a major role in the regulation of energy homeostasis and as been shown to vary according to physiological and pathological states.


Factors of neural origin play an important role in the control of energy homeostasis. Indeed central and autonomic nervous systems are involved in the regulation of whole body energy by regulating its different components: intake, expenditure and storage. The metabolic or secretory activity of various tissues or organ is indeed under the control of the autonomic nervous system. This is the case for the liver, the pancreas and the adrenal glands but there are data showing that this is true for muscles as well. The metabolic and secretory capacities of adipose tissues are also deeply controlled by sympathetic and parasympathetic nerves.

In most mammals, two types of adipose tissue, white and brown, are present. Both are able to store energy in the form of triacylglycerols and to hydrolyze them into free fatty acids and glycerol. Whereas white adipose tissue (WAT) provide lipids as substrates for other tissues such as muscles, brown adipose tissue (BAT) uses fatty acids for heat production. Over a period of time, white fat mass reflects the balance between energy expenditure and energy intake.

Remarkably body fat mass remains relatively constant in adult suggesting that food intake and energy expenditure are linked. This has been supported by numerous studies that demonstrated the inter-dependency of these parameters and thus a feedback loop between the brain and adipose tissues with the involvement of the autonomic nervous system on one side and that of sensory fibers and metabolites or hormonal signals on the other (Figure 1).


Figure 1 (above) :
Schematic representation of the feedback loop between the brain and adipose tissues. Brown and white adipose tissues are innervated by the autonomic nervous system, mainly sympathetic one. This will modulate both metabolic (lipogenesis, lipolysis and thermogenesis) and secretory activity of these tissues. Changes in circulating hormones and metabolites associated to sensory nerves originating from white fat pads will in turn signal to some brain areas the energy status of the organism.

How does the brain talks to adipose tissues ? and the role of the autonomic nervous system

BAT receives dense SNS innervation both at the level of blood vessels but also directly on adipocytes . It is demonstrated that each brown adipocyte receives one or more nerve endings. In WAT, the noradrenergic innervation fibres have initially been reported as closely associated with the blood vessels leading to its implication in WAT blood flow. Whereas data questioned this in the late eighties [5], it was in the nineties that Bartness and its group demonstrated, direct neuro-anatomical evidence for innervation of white adipocytes [6]. Furthermore they elegantly showed, using viral tracing methodologies that the inputs originate from CNS nuclei (paraventricular hypothalamus, noradrenergic tegmental system, caudal raphe region etc…) that are part of the SNS outflow.

The neurotransmitter involved is mainly norepinephrine although these nerves contain different neuropeptides among which neuropeptide Y or pancreatic polypeptide Y have been shown to control lipolysis.

Adipose cells express different noradrenergic receptor subtypes. In BAT, β-adrenergic receptor subtype (β3 in rodents) is the only one present and lipolysis is always activated when the sympathetic drive increases. In WAT it has been demonstrated that the lipolytic activity of adipocytes depends on a balance between lipolysis-promoting β-adrenergic receptor and lipolysis-inhibiting ⍺2-adrenergic receptor. Depending on this balance an increased sympathetic tone can lead to an increase or a decrease in lipolysis.

Most organs or tissues are innervated by both SNS and PNS. For a long time it was thought that white adipose tissues did not received parasympathetic nerves. Recent neuro-anatomical studies in rats have reported parasympathetic innervation of WAT. A physiological role of such input was proposed since vagotomy was shown to reduce the insulin-dependent glucose and free fatty acid uptakes.

Such role of PNS can be also sustained by the demonstration of the presence of functional nicotinic receptor on white adipocytes as well as an increased insulin sensitivity of these cells under nicotine stimulation. However the PNS innervation of WAT is highly controversial and remains a subject of debates.

Although adipose tissue is used as a general term, the fat pads are quite different in regards of their origin, anatomical characteristics and functions so that one should rather speak about white adipose tissues. Indeed both autonomic innervation and the number and affinity of the adrenoceptors of fat depots are heterogeneous.

First a relatively separated sympathetic innervation of inguinal and epididymal pads exist, since there are no overlapping patterns of labelled postganglionic cells within the sympathetic chain innervating these two deposits using fluorescent tracers. Viral tracers technologies suggest also differential innervation of fat pads for both sympathetic and parasympathetic nerves [7, 8,16,21]. Second, taking norepinephrine turn-over as an index of SNS activity, specific pattern has been delineated which might also depend of the stimulus considered.

Altogether these last data indicate a higher lipolysis in intra-abdominal fat pads as compared to subcutaneous one. Third, this is reinforced by the distribution of the different subclasses of receptors that depends on species, sex, and fat depot. Thus, in women, for example, it has been demonstrated that the number of ⍺2 and β1, β2-adrenoceptors varies between omental, abdominal and femoral adipose tissues and as a consequence the lipolytic response to epinephrine or norepinephrine.

The two main metabolic pathways of both white and brown adipocytes are on one hand the synthesis and accumulation of triglycerides and on the other their degradation into free fatty acid and glycerol. The increase in lipids store in adipocytes is performed by two ways. First by the direct uptake of triglycerides associated with lipoproteins coming from the circulation and which are hydrolized by lipoprotein lipase in non esterified free fatty acids.

These fatty acids are then transported into and in the cells by a family of fatty acid binding protein (FABP, FAT, FATP, aP2…). Second by the lipogenic pathways i.e. the de novo synthesis from glucose. This last one is transported into the cell mainly via the insulin-sensitive glucose transporter isoform Glut 4. The glucose allows the synthesis of pyruvate and glycerol-3-phosphate, substrates, which will lead to the synthesis of triglycerides. Indeed, pyruvate will be utilized for the formation of acetyl-CoA and then its transformation into malonyl CoA under the control of acetyl-CoA carboxylase. The last step catalyzed by fatty acid synthase, a multienzyme complex, leads to the formation of long chain fatty acids. These anabolic pathways are mainly under the control of insulin.

It is now recognized that lipolytic pathways is mainly under the dependency of three main players: adipose triglyceride lipase, hormone sensitive lipase, and perilipin A. In regards of metabolism the main differences between white and brown adipocytes is located downstream to lipolysis. Indeed in white adipocyte, both free fatty acids and glycerol are released into the adjacent blood vessels to provide fuel for other tissues. In brown adipocyte, free fatty acids will be oxidized by the cell itself.

The energy produced will be then dissipated as heat, thanks to the presence of a specific mitochondrial protein: the uncoupling protein 1. UCP1 confers to the mitochondria of brown adipose tissue their capacity of becoming uncoupled. As already mentioned above catecholamines and particularly norepinephrine are the main hormones involved in the control of lipolysis in both cell types. However one has to underline that, the antilipolytic effect of insulin is predominant and thus catecholamines exert their effect when insulin level is low. From what is said above it is easy to conclude that the sympathetic nervous system is the main driver for adipose tissues lipolysis.

Apart its well-known effect on lipolysis in both adipose tissue types and its effect on thermogenesis in brown adipose tissue, sympathetic nervous system plays a role in regulating the anabolic pathways. Thus it has been shown that stimulation of sympathetic nerves induces a dramatic increase in glucose uptake, utilization and lipogenesis in BAT but not in WAT. Whereas, as already mentioned, there are evidences that PNS innervation increases insulin sensitivity in WAT].

Over the last 20 years the notion has emerged that WAT is not only involved in the storage and release of energy but could also be part of other physiological functions due to its capabilities in synthesis and secretion of numerous factors such as leptin, adiponectin and many proteins involved in inflammation and immunity. So that adipose tissue is now considered as a true endocrine organ.

The synthesis and secretion of some of these compounds are under the control of numerous factors among which the sympathetic nervous system via catecholamines plays a role. Leptin control has probably been the most studied. There is numerous evidence that stimulation of β-adrenoceptor decreases the release of leptin. In human adipose tissue this occurs through a posttranslational mechanism, most likely secretion per se. In contrast, in rat adipose tissue, isoproterenol does not affect basal leptin secretion but has a short-term action to antagonize the insulin- stimulated leptin biosynthesis.

Although an elegant study demonstrates a decrease leptin secretion when 3T3L1 adipocytes (a well-characterized white adipose cell line) are cultured in the presence of primary sympathetic neurons. It has then been proposed that catecholamines may mediate short-term decrease in plasma leptin that occur within hours of fasting and cold exposure.

Adiponectin is also negatively regulated by β-adrenoceptor. By contrast the secretion of cytokines such as TNF⍺ and IL6 are increased under β-adrenergic stimulation. Overall these data suggest that upregulation of proinflammatory cytokines and downregulation of adiponectin by β-adrenoceptor activation may contribute to the pathogenesis of catecholamine-induced insulin resistance.

Fat mass is the result of two processes i.e. the regulation of the size and the number of adipocytes. We have shown that the autonomic nervous system is indeed involved in the first one by regulating both energy stores and thermogenesis in WAT and BAT respectively. There are also numerous evidence showing that the SNS is involved in the control of proliferation and differentiation and to a lesser of apoptosis of white and brown adipocytes (Figure 2).

Figure 2 (above) :
Schematic representation of the opposite effects of sympathetic nerve activity on proliferation and differentiation of brown and white adipose tissues. As an illustration the weight and DNA content are increased in denervated white fat pad (red column) compared to un-denervated control (blue column), demonstrating the inhibiting effect of the sympathetic tone on proliferation and differentiation of white adipose tissue (adapted from Cousin et al. 1993).

It is then well established than norepinephrine induces both proliferation and differentiation of brown adipocytes precursors in vivo and in vitro . Results observed after a decreased (denervation, noradrenergic blockade, hypothalamic lesion) or increased (β-agonist treatment, cold exposure) sympathetic activity lead to the same general conclusion.

By contrast sympathetic activation would inhibit the development of WAT. Norepinephrine inhibits proliferation of adipocyte precursor cells in vitro and can be blocked by propranolol, a general β-adrenoceptor antagonist. In vivo surgical denervation of WAT triggers significant increases both in rats and Siberian hamsters.

We have been the first to demonstrate that one week after denervation of one retroperitoneal fat pad, DNA content was largely increased without change in the number of mature white adipocytes. Furthermore, the amount of A2 COL6, an early marker of white adipocyte differentiation was enhanced in the denervated pad. One month later, the number of mature adipocytes was significantly increased in the denervated pad.

A recent study using transgenic mice having a massive reduction of innervation due to the lack of Nscl-2, a neuronal specific transcription factor, came in support of such observation. These mice present an increase preadipocytes number and a bimodal distribution of the size of adipocytes indicating an increase in the number of small adipocytes.

Although the importance of apoptosis in the biology of adipose tissues is still a controversial issue, there are different reports describing such process in both white and brown adipocytes. To our knowledge there is no direct demonstration of a role of the SNS in regulating the rate of apoptosis in adipose tissues, however several observations are in support of such role.

It has been demonstrated that the proapoptotic effect of TNF⍺ in brown adipocytes is abrogated by noradrenaline [46]. Furthermore noradrenaline protects these cells from apoptosis by phosphorylation and activation of MAP-kinase. Leptin like insulin induces a reduction of fat pad weight. This effect is observed both under peripheral or central injection of the hormones.

Furthermore it has been reported that adipocyte apoptosis occurs after intracerebroventricular administration of leptin in rats [48, 49, 50]. On the other hand it is well demonstrated that leptin induces an increased sympathetic nervous system activity. From these data, it is believe that the signal that promotes apoptosis under insulin and leptin CNS activation is probably norepinephrine or another co-secreted neurotransmitter.

Altogether, these results demonstrate that in vivo SNS innervation of WAT and BAT acts as modulator of fat cell development.

How adipose tissues talk to the brain

Energy balance is the result of ingestive behavior, energy expenditure and energy storage in adipose tissue. To explain the precise overall regulation of these parameters it has been hypothetized, at first by Kennedy in the 50th, that signals generated in proportion to body fat stores will act in the brain to modulate food intake and/or energy expenditure.

Among these signals the first to be proposed was insulin; since it was demonstrated that the pancreatic hormone acts in the CNS to reduce food intake [55,56]. Then leptin, the product of the ob gene was discovered and shown to play a major role in this regulation process. One has to stress also the role of nutrients of which the concentration might depend on the metabolic activity of adipose tissues such as glucose an free fatty acids.

Indeed both of these metabolites have been shown to play an important role as signals, reflecting energy homeostasis, to some part of the brain Glucose and lipids are detected by specialized fuel-sensing neurons that are incorporated in specific hypothalamic neuronal circuits. Hence, circulating nutrients cooperate with hormones, such as insulin, leptin, and ghrelin, to regulate the activity of distinct neuron populations that control food intake, energy expenditure, and glucose homeostasis.

Apart these circulating signals acting directly in the hypothalamus and other areas, adipose tissues sensory nerves may be part of this system. Indeed sensory innervation of WAT has been demonstrated by various facts. The identification of substance P and calcitonin gene-related peptide, markers of sensory neurons was a first demonstration. Then a direct neuroanatomical demonstration was given by use of anterograde tracer [62].

Finally the sensory projection to different brain areas, was extensively studied by Bartness et al. As stated by these authors, “labelling cells were found at all levels of the neuroaxis including both the nodose ganglia (visceral afferents) as well as the dorsal horn (spinal afferents) of the spinal cord and in almost all the autonomic outputs areas in the brainstem and midbrain”.

Although one does not know what (leptin, lipid molecules such as glycerol, free fatty acids, prostaglandins) these nerves “sense”, data are in support of their role in informing the brain on lipid stores. When selective destruction of sensory innervating epidydimal fat pad was performed in hamster by injecting capsaicin in one pad, the weight of the contra-lateral non-injected pad was increased in a degree that approximated the lipid deficit if the pad had been removed by lipectomy.


This review underlines the progress made over the years in delineating the relationships between the adipose tissues and the nervous system. Indeed data have clarified the neuroanatomical innervation of the different fat pads, the central localisation of their origin and their projections, the demonstration of sensory and parasympathetic innervation. This represents however new field that merits further attention since they are, as already said, a matter of debate.

The role of the autonomic nervous system in the control of adipose tissues functions has also received strong attention and led to new concept in regards not only to their metabolic and secretory activity but also to their plasticity. Considering plasticity, more data are needed to strongly sustain the influence of the SNS on apoptosis but also in the development of adipose tissue.

To determine whether nervous control could play a role in the fate of the different progenitors (stem cells, multipotent cells) which have been demonstrated to be present in adipose tissues and of which the role, the differentiation potential and their regulation is still poorly understood, appears crucial for a better understanding of adipose tissues biology and physiology.

Altogether this neural feedback-loop between adipose tissues and the brain plays a crucial role in the regulation of energy homeostasis and body fat mass. As it has been shown it could be altered in numerous metabolic pathologies such as obesity and type II diabetes, this represents an important areas of research with putative clinical implications.

You may be interested to know that an article on Water-Soluble Hormones vs Fat-Soluble Hormones is at

Hormones are chemicals (sometimes described as 'chemical messengers') that are produced and released by glands that form the endocrine system. There are many different hormones (see the list of hormones) that can be grouped together in different ways, e.g. according to which gland they are secreted by and which system(s) of the body they affect.

Some hormones dissolve in water (water soluble hormones) while other hormones dissolve in fats (fat-soluble hormones).

continued at the link just above ...
« Last Edit: June 15, 2019, 10:41:01 AM by Chip »
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