I have a confession to make: I am not a scientist. By inclination, education, and profession I am a health coach with a passion to write with solid research. Now, I’m going to discuss leptin and metabolic regulation. You’ll explore how leptin contributes its role in the regulation of different metabolic systems.

Let’s start ‘Leptin and Metabolic Regulation‘.

Leptin and Metabolic Regulation

You’ll see the interaction of leptin hormone with many other hormonal regulations to discuss the different aspects of leptin and metabolic regulation in detail.

Thyroid Regulation:

The basics of metabolic thyroid regulation were presented in Leptin and Thyroid. However, we will review and expand on the evidence presented in that installment to develop a fully functional model of thyroid hormone regulation.

Thyrotropin Releasing hormone (TRH) secretions by the PVN are regulated directly by Neuropeptide Y (NPY), Melanocyte Stimulating Hormone (MSH), and GABA, with NPY playing the most important role. As a consequence TRH secretions are regulated indirectly by leptin, glucose, and insulin. Because the metabolic triumvirate of leptin, glucose, and insulin ultimately control GABA, NPY, and MSH, one may be tempted to simplify this model by relating thyroid output directly to leptin, glucose and insulin. However, NPY must remain present in the model for reasons that will become clear when we examine the physiological abnormalities of the obese.

Both VMH/Hepatic derived GABA and Lateral Hypothalamus (LH) derived NPY suppress the release of TRH in the PVN (1). ARC derived MSH potently promotes TRH release. This makes a lot of sense when you think about it. GABA and NPY are going to be inversely related in normal people. When leptin levels are normal NPY will be suppressed and alpha-MSH will increase in the ARC. This will serve to increase TRH production. Leptin also decreases VMH/Hepatic-derived GABA delivery to the PVN, thus further increasing TRH production. So in this state TRH levels stay in the normal range. In this state leptin is suppressing TSH secretion from the pituitary and strongly stimulating Thyroxin secretion from the thyroid gland (2). Thus we end up with normal thyroid hormone levels.

The regulation of Thyroid Stimulating Hormone (TSH) secretion is depicted in figure 7.1. TRH, leptin, and Thyroid Hormone (T4/T3) directly regulate the secretion of TSH. The synchronicity of plasma TSH and leptin levels demonstrates leptin’s position as TSH’s most potent regulator (4).

Thyroxin secretion is modulated directly by leptin and TSH in the thyroid gland. Either may be the dominant metabolic regulator depending primarily on plasma leptin levels. The TRH, TSH, Thyroxin loop is a redundancy in case metabolic regulation by leptin is not present. Thus when plasma leptin levels are in the normal range, leptin is the prime thyroid regulator, however when leptin levels are very low or very high TSH becomes the dominant signal.

Adrenal Regulation:

Corticotrophin Releasing Factor (CRF) secretions for the PVN are controlled directly by CRF, NPY, GABA, Nor-Epinephrine (NE), Arginine-Vasopressin (AVP) and leptin.

CRF promotes its own release (5,6). Injection of either CRF or a beta-adrenoeceptor (B-AR) agonist in to the PVN of rats promotes CRF secretion by altering DBH protein in the neural bundles (6). Sympathetic Nervous System (SNS) projections run from the spinal column and the basal sympathetic nodule directly to the PVN. These neural circuits sense immunological stress, physiological stress, or stimulants.

In vivo, most regulation is accomplished by the alpha2-adrenoreceptor (A2-AR) and not the B-AR. NE binding to A2-AR sites in the PVN dramatically increase CRF production (7). The effects of NE on the PVN are not temporary either. By altering DBH protein in the neural bundles the PVN is sensitized to activation of the Hypothalamus – Pituitary – Adrenal (HPA) Axis. The effects of direct injection into the PVN of rats lasted 3 weeks. The effects may have lasted even longer, however at this time they had terminated the rats to examine their brains (6).

NE is also delivered to the PVN by afferent projections from the Locus Coeruleus (LC) (8). The LC is an extremely complicated neural structure. It is extensively studied as abnormalities in the LC often result in psychological disorders. For our purposes we may consider the LC to be the psychological stress response center.

The LC is one of the brain regions that is strongly correlated with brain wave patterns. This is one reason that even small amounts of sleep depravation result in highly elevated levels of corticosterone and cortisol. When we enter slow wave sleep patterns, NE delivery to the PVN is reduced. It is also reduced during times when we do not have to pay very close attention to things. NE release from the LC is strongly correlated with attention, vigilance, and psychological stress. Thus we can conclude that brain wave patterns are a pretty good indicator of NE activity in the PVN.

Leptin directly increases corticosterone and epinephrine production through multiple pathways. First by lowering VMH derived GABA delivery to the PVN it increases firing rate in the PVN, resulting in increased CRF secretion. Leptin also enhances secretion of AVP (9). It further upregulates the V1 AVP receptor, promoting additional CRF release from the PVN (10).

AVP and CRF act at the pituitary to increase adrenocorticotropin (ACTH). However their effect is not additive, but is in fact synergistic. AVP strongly potentiates CRF-induced release of ACTH. Thus leptin is a potent activator of the HPA.

NPY is very important for the regulation of CRF and TRH (12). The PVN can operate in either pro-TRH mode or pro-CRF mode. In pro-TRH mode, activation of the PVN, by reduction in GABA levels, causes more TRH to be released. However in pro-CRF mode activation of the PVN, again through GABA, results in increased CRF production. This behavior is controlled by NPY. The main regulator of TRH production from the neuron’s perspective is alpha-MSH. Alpha-MSH enhances the phosphorylation of CREB (PCREB), which promotes TRH secretion. NPY determines the specific neurons in which PCREB accumulates. So alpha-MSH does not really promote TRH secretion; its role is to restrict the enhancement of PCREB levels. When injected in the PVN of rats, NPY altered the cellular CREB levels of the pro-TRH neurons versus those in the pro-CRF neurons. In the pro-TRH neurons it reduced CREB levels, while in the pro-CRF neurons it elevated CREB levels. So when alpha-MSH was applied it produced an increase in PCREB in the CRF neurons, leading to enhanced CRF secretion.

Sex Hormone Regulation:

Sex hormones are primarily regulated by estrogen and metabolic state. Both excess estrogens and the fasted hypoglycemic state can drastically reduce sex hormone levels. Emerging evidence calls into question the significance of the Hypothalamic – Pituitary – Testicular Axis (HPTA). In my opinion the HPTA is only of real significance when one is utilizing supraphysiological amounts of testosterone.

Estrogen modulates the secretion of Leutinizing Hormone Releasing Hormone (LHRH or GnRH). It does this by binding the beta-estrogen receptor (B-ER). Unlike the singular androgen receptor, there are multiple estrogen receptors. The B-ER is mostly expressed in the dorsal region of the PVN. By binding to the B-ER in the dorsal region of the PVN, estrogen can lower LHRH secretion. The true significance of estrogen-induced suppression of LHRH is suspect, however.

This is because metabolic state also plays a large part in determining sex hormone levels. Increased CRF or NE delivery to the PVN directly reduces the amount of LHRH produced by the neurons in the PVN. As a result, psychological stress, physiological stress, or stimulants possess the ability to reduce LHRH secretion. Both CRF and NE accomplish this feat by increasing B-ER density and sensitivity in the dorsal region of the PVN (13).

We all know stress can reduce natural testosterone production, but it is not often discussed that fasting also decreases testosterone. The fasting induced decrease is mediated by several mechanisms (14). In the short term when the stomach is empty the afferent vagal nerves are innervated. These nerves connect directly to the medulla oblongata. The medulla oblongata has nor-adrenergic nerve projections running to the PVN. Activation of the medulla oblongata results in increased NE delivery to the PVN, which in turn upregulates B-ER receptors and leads to suppressed LHRH.

If caloric restriction is continued the SNS is eventually activated, leading to even more NE release, further exacerbating the problem. Caloric restriction also increases NPY; an increase in NPY promotes CRF secretion, further lowering the setpoint for estrogens. This ultimately leads to a decrease in LHRH, and hence a reduction in LH and FSH, causing reduced testosterone secretion from the testes.

What really calls into question the HPTA’s very existence is that a reduction in LHRH production is not even necessary for metabolic state to reduce testosterone production in the testicles (15). In a very interesting experiment, the PVN of rats were injected with CRF or a beta-adrenergic agonist. They then administered human chronic gonadotropin (hCG). What they discovered was that injection of those compounds into the PVN attenuated the testicles’ response to hCG.

To determine how the PVN was directly manipulating the testicles, the scientists employed a pseudo rabies viral tracer and found that there exist direct efferent nerves running from the PVN down to the testicles. To ensure they were correct, the scientists lesioned the PVN of some of the rats. They found that by damaging the receptor surface of the PVN, they ameliorated CRF or beta-adrenergic attenuation on hCG-induced testosterone secretion.

What this means is that the pituitary and hence blood levels of LH and FSH can be taken out of the loop. The PVN can directly control the leydig cells in the testes.

Leptin and Hormones regulation

Sympathetic Nervous System:

The Sympathetic Nervous System (SNS) is actually quite complicated. As evidenced above there are numerous nor-adrenergic projections from various brain regions used for compartmental communication. However if we restrict our interpretation of the SNS as those neurons that deliver catecholamines to the body then its analysis is simplified. The resulting SNS can be divided into two distinct sections.

One I will call the metabolic branch. This branch of the SNS delivers NE to the pancreas, kidney, liver, adipose tissue, and muscle tissue. The second segment is fight/flight branch. This branch is not innervated by the metabolic state of the PVN. Instead it’s innervated by the LC, which is the brains stress response center. Stressors like fight/flight stimuli, heat shock, or ephedrine activate both branches, whereas metabolic regulation by the PVN only activates the metabolic branch.

Activation of these branches is accomplished through low-level dopamine stimulation (16). Dopamine is technically an excitatory neurotransmitter. However in the body it can end up being a relaxant in some cases, as high levels of dopamine reduce NE’s stimulatory effect on neurons. Additionally high levels of dopamine suppress vasopressin and glutamate activation of SNS neurons (17,18). The PVN or the LC delivers low-level dopamine to the various branches of the SNS, which in turn promotes NE release. Leptin increases SNS activity by increasing nerve firing in the PVN, the result of which is enhanced dopamine delivery to the spinal cord.

Because of this strange phenomenon, different segments of the SNS can be regulated quite differently based on metabolic state. This effect will become more important when we discuss obesity later on.

Pancreatic Regulation:

The pancreas is regulated directly by NE, leptin, glucose, insulin, and GABA. NE and glucose however play the most important role. Both leptin and NE prevent calcium influx into the beta cells and thus attenuate insulin release. Glucose, by closing potassium sensitive ion channels, promotes depolarization and calcium influx, leading to insulin and GABA co-secretion (19).

The pancreatic beta cells posses both the insulin-independent GLUT2 and the insulin-dependent GLUT4 glucose transporters. When glucose is transported in via glut it promotes insulin release. Insulin then binds to the neighboring beta cells and further increases beta cell glucose uptake. Because of this feed forward amplification pathway, insulin promotes its own release. This amplification is partially responsible for the different phases of insulin release; it also allows for a sudden and dramatic increase in insulin output as seen during phase one of insulin release.

This rapid amplification would go on indefinitely if it weren’t for two things. First, if the dramatic insulin release in phase one is sufficient to drive down blood sugar, then there is no stimulus to continue insulin secretion. In subjects with hyperglycemia this does not happen. In this case the beta cells are being overdriven. When this happens the beta cells start to secrete there own leptin. They use this leptin to become insulin resistant. This prevents serious damage and cell death of the beta cells and islets.

Thus at this point we enter phase two of insulin release. Phase two tends to be much lower but has a longer duration. The pancreas co-secretes the peptide GABA whenever it secretes insulin. It has been hypothesized that the secretion of GABA is responsible for the reduction in glucagon release seen during times of elevated insulin (20).

By binding to any of the adrenoreceptors, NE reduces insulin secretion from the beta cells by preventing calcium influx.

Renal Metabolic Control:

The kidneys play an important role in regulating blood glucose, blood pressure, and plasma leptin levels. In the hypoglycemic state glucose is transported across a concentration gradient in the proximal tubular cells, via sodium-linked glucose transporters. This results in filtered glucose being completely reabsorbed. Renal glucogenesis also plays an important role in preventing hypoglycemia by contributing to blood glucose levels (21).

Elevated blood pressure can affect metabolic regulation in several ways. By restricting blood flow, elevated blood pressure can reduce glucose disposal in adipose and skeletal muscle tissue. Thus an important feature of the hypoglycemic state is often elevated blood pressure. There does also appear to be marked sexual dimorphism in this aspect of metabolic regulation. Leptin, through interactions in the VMH and PVN, increases SNS outflow to the kidneys. In men this often results in elevated blood pressure by causing increased activity of the Rennin-Angiotensin System (RAS) as well as decreased sodium excretion. The sexual dimorphism has been attributed to altered alpha-adrenergic receptor iso-form distribution (22). Men often express the alpha iso-form of the A2-AR. This iso-form of the receptor, when activated by said SNS segments, results in elevated blood pressure.

It has been proposed that in women this phenomenon is less common because elevated blood pressure could be damaging to a developing fetus. Leptin normally balances out this effect via direct interaction with the JAK2/STAT3 pathway in the kidneys. This activation elicits a diuretic result (23). Thus, directly leptin acts as a diuretic, however its effects though the SNS increase blood pressure and increase renal glucose re-absorbtion.

The kidneys are also the prime sites for leptin disposal (25). It has been proposed that the kidneys remove up to 80% of leptin—both free and bound—from the blood stream. This appears to be a saturable phenomenon, restricted primarily by blood flow to the kidneys. This is yet another reason men exhibit lower leptin levels than women, as blood delivery to the kidneys in men is roughly 50% greater than in women. The effects of the kidneys in maintaining plasma leptin levels can be seen in patients with late stage renal failure. Such individuals exhibit hyperleptimania in spite of the fact that they generally lose weight and reduce caloric intake.

Saturation in the kidneys may also play an important role in the elevated leptin levels seen in the obese. Plasma leptin levels increase exponentially with relative body fat increases. Yet obese people do not posses an exponentially greater number of fat cells. In addition, the adipose cell hypertrophy that accompanies obesity is known to slightly reduce leptin secretion. Thus it is possible that reduced renal leptin degradation may play a role in the elevated plasma leptin levels seen in the obese.

VMH Leptin and Glucose Sensor:

The VMH is the brain’s main leptin and glucose sensor. As discussed in Leptin: The Next Big Thing V, the KIR neurons in the VMH sense brain glucose concentrations. The VMH is specifically suited to this task because of its location—it is extremely close to the endothelial cells. The VMH can literally keep tabs on blood glucose directly, whereas the rest of the brain relies on brain glucose transport across the blood brain barrier (BBB). Additionally, the VMH is comprised of basically the only neurons in the brain that posses GLUT4 glucose transporters. As a result, insulin can further drive glucose signals in the VMH.

Hepatic Glucose Sensor:

It has long been known that modulating the liver’s glucose supply alters firing rates in different regions of the brain, yet only recently has the mechanism been identified (26,27). Using viral tracers, scientists were able to determine that there are afferent nerve connections running from the liver directly to the PVN. These nerves serve to deliver GABA to the PVN and thus slow its firing rate, just as the VMH does. This makes sense, as the liver is a great barometer of blood glucose levels. It can relay this information directly to the PVN and reduce hypoglycemic response if it feels it’s not warranted. The liver possesses GLUT2, GLUT4, and the fructose-specific GLUT5 transporters. Because of this fructose can activate the hepatic glucose sensor, whereas it cannot activate the glucose sensors in the rest of the body.

Portal Vein Glucose Sensor:

There is also the portal vein glucose sensor to contend with. Many studies often mix up the effects of the portal vein and the hepatic glucose sensors, as they are very close to one another. Recently it has been shown that they are indeed separate systems, though because of location activation of one generally entails the activation of the other. Fructose however highlights why the two cannot be lumped together.

The portal vein glucose sensor is responsible for non insulin-stimulated glucose disposal seen in the post absorptive state. If you infuse the portal vein with glucose you can induce hypoglycemia in rats—an effect specific to the portal vein. It is known that this response depends on GLUT4 and AMPK, however it does not depend on insulin, as insulin receptor knockout mice still display this behavior. It is unknown at this time what the mechanism of action is, though a likely candidate is glucagon, as glucagon strongly stimulates AMPK and can lead to insulin-independent glucose disposal.

The portal vein glucose sensor only expresses the non insulin-dependent GLUT2. It is known that there are afferent nerves running from the portal vein glucose sensor to the adrenal medulla. These nerves serve to deliver GABA to this brain region and reduce the secretion of corticosterone (27).

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