Você está na página 1de 7

Murstig 1!

Is Hyperleptinemia a Cause or Symptom of Leptin Resistance?

The hormone leptin is well understood to be part of the regulation of fat in the body. Obesity has

been shown to be highly correlated with high levels of leptin in the bloodstream, a condition known as

hyperleptinemia. There are conflicting studies whether the elevated levels of leptin causes a resistance to

the hormone and thus induces an obese state. An alternative view is that hyperleptinemia is merely the

reaction to the high levels of adipose tissue during obesity, which is caused by leptin resistance. Further

complicating the determination of the leptin resistance is recent information pointing to diets and

components in the diet being a potential cause. There appears to be more information opposing the idea

that hyperleptinemia is the direct cause of leptin resistance (9).

The discovery of leptin in 1994, the first adipokine, is an adipose signaling molecule that has

changed our knowledge of energy homeostasis. Its discovery has illuminated the hormone responsible for

the feedback loop between fat stores and the brains control of energy consumption. It has increased

expectations for the potential treatment of obesity. This polypeptide hormone, is primarily white adipose

derived and largely takes action on specific populations of neurons in the arcuate nucleus of the

hypothalamus. Leptin levels tell the brain how much energy is reserved, specifically, the amount of

triacylglycerols that are in the adipocyte. Leptin provides important signals in the regulation of body

weight and energy balance and as an anorexigenic hormone, it suppresses appetite and affects both

metabolic rate and body temperature. Leptin also has a mechanistic role in peripheral interactions by

regulating reproductive function, bone metabolism, cardiovascular regulation, and improving

immunization.

Placenta, mammary glands, ovaries, skeletal muscle, stomach, pituitary gland, lymphoid tissue,

and brown adipose tissue all have the capability to secrete leptin (2). However, the largest expression of

leptin is secreted by adipocyte cells and released into circulation. The amount of leptin in the blood

plasma is proportional to the level of fat mass in the body. The choroid plexus is the entry point for leptin

where it crosses the blood brain barrier into the hypothalamus. Once in the hypothalamus, signals are sent

to different sites in the brain that regulate various operations in the body. The arcuate nucleus is the

primary regulatory region in the hypothalamus. There are two primary subpopulations of neurons within
Murstig 2!

the arcuate nucleus, the pro-opiomelanocortin, (POMC) neurons and the agouti-related protein (AgRP)/

nureopeptide Y (NYP) neurons. Leptin uses a receptor-mediated process and acts upon these specific

neuron populations to control food intake. It stimulates a cascade of expressions in the hypothalamus,

increasing energy expenditure and decreasing body weight.

In individuals with hereditary loss of leptin, structural defects of this hormone or its receptors are

accompanied by obesity, and for these rare individuals, leptin replacement therapy can induce weight loss

(1). However, leptin reducing responses have not been shown to be the case in individuals with the more

commonly occurring diet induced obesity (DIO). For these individuals, elevated plasma leptin levels are

circulating in the bloodstream with decreased leptin sensitivity, causing the condition of hyperleptinemia.

An acquired loss of leptin neuronal signal response coexists with hyperleptinemia in obese individuals

and has been shown to provide a tendency toward progressive weight gain (3). This disrupted leptin

response is called leptin resistance and its mechanism remains poorly understood. Research has suggested

multiple mechanisms for impaired leptin transport. These include limited capacity to transport leptin

across the blood brain barrier to reach its neuronal targets (7), disruption of the neuronal signaling

cascade within specific regions of the brain, increased expression of pro-inflammatory cytokine signaling

(8), and altered neuronal plasticity. Understanding these mechanisms and how to restore leptin sensitivity

for these individuals could potentially move us closer to treating obesity.

Leptin resistances relationship to hyperleptinemia was explored in a study, where obese mice

were given a high fat diet to create the conditions to test the response to manipulated leptin levels (3). The

study found that after prolonged exposure to a high fat diet, the mice no longer responded to leptin

changes even when they were induced directly into the brain. This indicated that the neurons in the brain

had impaired ability to control the energy intake of the body. The authors propose that the chronic

hyperleptinemia causes overstimulation of the receptors and block further signaling. Alternatively, they

indicate a fat blockage of leptin signaling could also be responsible via stress and inflammation of

endoplasmic reticulum within the hypothalamus. An additional test was performed where the authors

clamped the plasma leptin levels of the mice to normal wild (unmodified) mice leptin levels, yet fed them

a high fat diet. The mice became obese however, varying the leptin levels still allowed some form of

energy management indicating that they were not leptin resistant. The authors conclusion in this study
Murstig 3!

was that hyperleptinemia is a requirement for leptin resistance, and that dietary fat alone cannot create

this condition.

A counter opinion can be found in another study (10) that was performed on polyphagia

(excessive hunger) induced obese rats that developed hyperleptinemia. These rats were tested against

normal control rats where they were all allowed to eat a normal diet resulting in the polyhpagia rats

becoming obese. The rats were then given a calorie restricted diet and plasma leptin levels were

monitored allowing the measurement of leptin resistance of the control and the polyhpagia rats. The

polyphaiga rats did not appear to develop leptin resistance, and the authors infer that hyperleptinemia may

actually be a response by the body to combat DIO. This directly opposes the idea that hyperleptinemia is

a cause of leptin resistance.

Another opposing view regarding hyperleptinemia as the root cause of leptin resistance is that

leptin supplementation treatment on its own has not been shown to be an effective measure to reverse

leptin sensitivity in individuals with obesity. However, a recent study performed on mice suggests to

target the POMC neuronal pathways with elevated levels of long-acting leptin (6). This was performed by

initially silencing the POMC gene expression in the arcuate nucleus of the hypothalamus for

approximately 8-12 weeks. POMC controls feeding behavior and energy expenditure by regulating energy

balance. Silencing of the POMC, in addition to calorie-restricted eating, resulted in weight loss. A high

dose of leptin therapy was supplied after maintaining weight loss through calorie restriction and reduction

of endogenous leptin, this would help to regulate body weight set points in order to control obesity more

efficiently. This appears to show that hyperleptinemia is mostly an indicator of the fat stores in the body

and that the resistance can be affected by other means.

Recent studies have shown that leptin resistance may actually be dependent on the diet contents

and amount of time within that diet. One proposed novel method to reverse leptin sensitivity is to restore

the leptin signaling in neurons by over expressing afferent peptides and repressing efferent peptides to

affect food consumption (4). This report assumes leptin resistance is a consequence due to leptin transport

impairment across the blood brain barrier (BBB). Specific nutrients and food components have been

described to promote leptin transport thus reducing hyperleptinemia. Phenolic compounds from natural

resources were suggested due to their ability to reduce circulating plasma leptin levels. Some of the
Murstig 4!

compounds include resveratrol from grapes and wine, oleuropien from olives, myricetin from vegetables,

plums, peaches, pecans, tea, red wine, berries and carnosic acid from rosemary extract. Other compounds

that have been proven to reduce leptin resistance in humans (5) include terpenes such as lycopene (from

tomatoes and watermelon), saponins from tea, and the polyunsaturated fat, conjugated linoleic acid. These

food compounds, (mainly polyphenols), have been suggested to improve leptin sensitivity by targeting

hypothalamic signals and transport across the blood brain barrier.

Targeting POMC is thought to be a potential treatment pathway to lessen leptin resistance effects.

Teasaponin is one such treatment that appears to address the POMC pathway. A study performed at the

University of Wollongong in Australia demonstrates that teasaponin was found to have a dramatic effect

on weight loss in diet-induced obese mice (11). Teasaponin appears to act on the POMC neurons while

not affecting the AgRP/NPY neurons, thus reducing appetite. Additionally, the teasaponin also was found

to affect the PYY hormone, which increases satiety. Interestingly, in this review, additional studies were

performed to look at the potential effect of teasaponin on glucose intolerance and insulin sensitivity.

Blood glucose level tests were performed and it was found that teasaponin treated mice had lower glucose

levels than the control group. The teasaponin mice also exhibited reduced insulin resistance. The study

also examined studied leptin levels for teasaponin treatment where they found that hyperleptinemia was

reduced. The inspiration for this study was to look at tea and its historic usage for treating inflammation

in the body. This is an example of using food to address obesity and its symptoms.

Leptin is a critical hormone in the control of body weight and its relationship to fat stores is well

understood. However, the mechanisms involved in the regulation of food intake relative to leptin levels

are complex and are affected by many variables. Hyperleptinemia, the excessive levels of leptin in the

bloodstream, in most cases is related to obesity, and its role in leptin resistance is still under debate. There

appears to be ample evidence that several mechanisms are involved in the resistance and not the mere

presence of elevated levels. The tests that were specifically targeting the hypothalamus neurons POMC

and AgRP/NYP appear to have substantial impact on leptin resistance. This supports the case that the

leptin levels are not directly causing leptin resistance but rather a neuronal failure to properly respond to

the leptin levels.


Murstig 5!
Murstig 6!

References

1. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, et al. (1999) Effects of recombinant

leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341: 879884.

2. Margetic S, Gazzola C, Pegg GG, Hill RA (2002). "Leptin: a review of its peripheral actions and

interactions". Int. J. Obes. Relat. Metab. Disord. 26 (11): 14071433. doi:10.1038/sj.ijo.0802142.

PMID 12439643.

3. Knight ZA, Hannan KS, Greenberg ML, Friedman JM (2010) Hyperleptinemia Is Required for the

Development of Leptin Resistance. PLoS ONE 5(6): e11376. doi:10.1371/journal.pone.0011376

4. Gerard Aragone` s, Andrea Ardid-Ruiz, Maria Ibars, Manuel Suarez and Cinta Blade (2016)

Modulation of leptin resistance by food compounds. Molecular Nutrition Food Resources 2016, 60,

17891803 DOI 10.1002/mnfr.201500964

5. 6. Belury, M. A., Mahon, A., Banni, S., The conjugated linoleum acid (CLA) isomer, t10c12- CLA, is

inversely associated with changes in body weight and serum leptin in subjects with type 2 diabetes

mellitus. J. Nutr. 2003, 133, 257S260S.

6. Chhabra KH, Adams JM, Jones GL, Yamashita M, Schlapschy M, Skerra A, Rubinstein M, Low MJ.

Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin

sensitivity and Pomc gene expression reverts extreme obesity. Molecular Metabolism. 2016;5:86981.

7. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, et al. Decreased

cerebrospinal- fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet

1996;348(9021):15961.

8. Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, et al. Leptin regulates

proinflammatory immune responses. FASEB J 1998;12(1):5765.

9. Neira Sinz a, Jaione Barrenetxe a, Mara J. Moreno-Aliaga Jos Alfredo Martnez. Leptin resistance

and diet-induced obesity: central and peripheral actions of leptin. Metabolism. 64: 2015, 35-48.

10. Ying Han a, Yeonsoo Joe b, Eunhui Seo b, Sa Rah Lee c, Mi-Kyoung Park, Hye-Jeong Lee b, Duk

Kyu KimThe hyperleptinemia and ObRb expression in hyperphagic obese rats. Biochemical and

Biophysical Research Communications 394 (2010) 7074


Murstig 7!

11. Yinghua Yu, Yizhen Wu, Alexander Szabo, Zhixiang Wu, Hongqin Wang, Duo Li, and Xu-Feng

Huang. Teasaponin Reduces Inflammation and Central Leptin Resistance in Diet-Induced Obese Male

Mice. Endocrinology. June 10, 2013 doi.org/10.1210/en.2013-1218