Stress

The stress pathways in the body center on the hypothalamic pituitary adrenal axis (HPA). This complex system has multiple pathways that result in a myriad of responses to various situations. To understand the effects of stress on the hunger/metabolic rate system it is first necessary to understand how the HPA axis functions in humans. There are three types of negative feed back loops to the HPA axis, a fast, an intermediate and a slow loop. The fast system occurs within seconds of stimulation of the CRH neurons in the brain. It involves the release of a chemical called glutamate which turns off the CRH producing cells. Of note, this immediate stress turn off valve is dysfunctional in depression. The slow system, takes days to occur. This feed back loop decreases the anterior pituitary release of ACTH in response to CRH stimulation. This intermediate response also effected by two other hormones, vasopressin and oxytocin. Vasopressin is a hormone that is important in sensing hydration status and oxytocin is important in breastfeeding and inducing labor. The slow system of feedback involves the adrenal glands becoming less sensitive to ACTH and occurs over months.

So what are the effects of chronic stress on the HPA axis and how do those effects influence appetite? Human models to assess the effects chronic stress are few, but the one most commonly studied has been post traumatic stress disorder. The effect of PTSD on the hypothalamic pituitary adrenal (HPA) axis has been controversial but most studies show patients with PTSD have suppressed cortisol and elevated corticotropin (CRH) levels. It has been shown that emotional stress and peripheral pain both increase CRH production. Chronically elevated CRH feeds back on the limbic system, which controls emotion, and results in an even greater CRH release. Thus chronic stress not only increases CRH, but also increases the CRH response to acute stressors in those with chronic stress. The elevated CRH results in increased ACTH and then increased cortisol. Cortisol has been shown to increase appetite. Depression, obesity, and hyperinsulinemia have all been shown to enhance this process making stress related weight gain worse.

NPY (neuropeptide Y) levels have been shown to be elevated in diet induced obesity. NPY stimulates CRH release, thus increasing CRH levels. As mentioned increased CRH results in an increase in limbic stimulation of CRH in response to stress. CRH elevations have other effects as well. CRH in the periphery increases leptin production, further aggravating the leptin resistance of obesity. Thus in obese people they will have an augmented response to stress and that response makes the underlying process of obesity's toxicity worse.

Another key factor in the responsiveness of ACTH to CRH is estrogen. Estrogen decreases the response of the POMC cell of the anterior pituitary to CRH. This has been shown to affect response to stress induced feeding behavior as well. Thus men and estrogen un-replaced menopausal women have a greater tendency to respond to chronic stress with an increase in appetite. This may explain some of the cravings associated with menses and the weight gain common with the onset of menopause.

Chronic stress is associated with elevated levels of norepinephrine. Norepinephrine acts by two separate mechanisms to increase ghrelin production. NE works directly in the stomach to stimulate ghrelin release and NE acts on the vagus nerve to increase vagal tone, again increasing ghrelin release. More ghrelin means more hunger and more NPY release by the AGRP/NPY cell. CRH neurons in the locus ceruleus increase NE and may be important in worsening of anxiety and stress conditions. This may be another pathway by which obesity induced elevations in CRH would increase the response to both acute and chronic stress.

Chronic stress also acts in the brain to decrease serotonin. Serotonin acts in the brain to enhance the effects of leptin in the hypothalamus. Less serotonin acts to decrease the effect of leptin which results in less satiety and lower metabolic rates. Chronic stress leads to decreased dopamine in the brain, especially in the addiction center (nucleus accumbens). Chocolate, a dopamine enhancing food, (which none of us of course ever eat when we are stressed) increases dopamine levels in this addiction center, but in the processes creates an addictive behavior reinforcing that reach for the Hershey’s bar. But the chocolate also acts on the cannabinoid receptor (CB1). Increased CB1 results in a decreased action of leptin which leads to more stimulation of the AGRP/NPY cell and lower metabolism and more cravings.

With so many chronic stress pathways contributing to cravings, hunger and lower metabolic rate, it is next to impossible to try and restrict calories and get in enough glucose to still suppress the hunger. If you do manage to get enough glucose to suppress the hunger, chances are you won’t have enough calories left over before reaching your caloric limit. Thus you won’t be able to get in enough fat to keep that hunger suppressed until the next meal. In addition stress response pathways linked to specific “comfort foods” are wired into our addiction centers in response to stress, guaranteeing we won’t stick to our dietary plan. Anyway you look at it; chronic stress makes calorie restriction very, very difficult.

The only effective way to address this issue is to go after it at its source, the stress itself. Chronic stress can be divided up into different precipitators that are important to recognize in order to begin treatment. Stress usually comes from either an external source (trauma, violence, abuse, financial difficulties, relationships, family illness/separation) or an internal source (self esteem, anxiety, phobias). It can be further divided into past, present and future times that the precipitating events/thoughts exist in for the individual. Response to treatment depends on a host of factors including intensity and repetitiveness of the event, educational level of the individual, presence or absence of support systems, and many more. Multiple modalities from cognitive therapy to behavioral therapy to prescription drugs to hypnosis to meditation and combinations of these and more have all been shown to have some efficacy.

Depression

The treatment of the serotonin based psychiatric conditions of depression, anxiety and obsessive/compulsive disorders (OCD) has been revolutionized with the discovery of a class of drugs called selective serotonin reuptake inhibitors (SSRIs). Serotonin works by being released at the end of a nerve cell in the brain and then binding to the connecting nerve cell triggering it to fire. The serotonin is then reabsorbed by the first cell so it can be reused again. In cases of depression, anxiety and OCD there is not enough serotonin for one cell to cause its connecting cell to fire. Thus the whole system is dampened. The SSRI medications slow down the reuptake of the serotonin when it is released. Thus the connecting nerve is exposed to more serotonin for a longer time increasing the chance it will fire. That is how the SSRIs work.

What are the implications for this when it comes to the leptin/ghrelin system? Remember that serotonin acts on the POMC cell to increase the effect of leptin. So initially when you take an SSRI, serotonin levels rise and leptin becomes more effective, thus decreasing appetite and increasing metabolism. So initially, SSRIs should cause weight loss and that is exactly what is seen. But after time, 3-4 months, the serotonin receptors on the POMC cell start to down regulate. The result is then a decrease in leptin’s effectiveness and weight gain. Again this is exactly what is seen with the SSRIs, weight loss at first followed by weight gain. Knowing this, can we devise a system to avoid the weight gain while still being able to treat the underlying depression, anxiety and OCD conditions? Perhaps, but it is not easy.

If you have depression and respond to an SSRI, studies show there is a 70% chance of a relapse if you come off the medication after you have been on it and responded. So most people end up needing to take SSRIs on a chronic basis, therefore just stopping treatment is not a great option. An option that could work would be to cycle the SSRI with non SSRI medications like dopamine agents (Wellbutrin) or other non serotonin medications for 4-6 weeks so that the serotonin receptor at the POMC would up regulate again, allowing the SSRI to be restarted and still result in weight loss. Studies to confirm this theory still need to be done.

Another idea is to add medications that would inhibit CB1 thus countering the effect of the serotonin on the POMC cell. The first CB1 antagonist, rimonabant will probably be on the market by 2006. Studies on its effectiveness in mediating the SSRI induced weight gain will be very helpful. Much research is needed now that we understand how the SSRIs affect hunger in order to allow this valuable class of medications to be used without swinging the scales in favor of the obesity epidemic.

Pain

Chronic pain creates four interlocking vicious cycles that contribute to obesity and then on top of that increases the toxicity of the obesity it helped to create. Chronic pain is truly a huge player in the obesity epidemic. The story unfolds like this.

Obesity transmits more force on the joints contributing to more traumas and thus more pain. The heavier you are the more likely you are to fall or twist an ankle etc., again leading to more pain. The pain makes you more sedentary which in turn lead to fewer calories burned and more obesity.

Obesity leads to increased fat cells which produce more leptin. Leptin in turn generates more leptin resistance and the output from the POMC cell drops. The POMC cell makes beta endorphin a natural pain killer. So as output drops the body becomes more sensitive to pain. Increased pain again makes you more sedentary which again leads to more obesity.

Pain leads to difficulty in perpetuation of the normal sleep cycles. This lowers nighttime leptin and decreases metabolic rate leads to more obesity. More obesity leads to more traumas and more pain. Pain leads to decreased serotonin levels which lead to more leptin resistance on the POMC cell. This leads to increase hunger and decreased metabolism and more obesity.

More obesity leads a decreased self image and more depression which further decreases serotonin and leads to more pain. As mentioned chronic pain leads to a reduction in natural endorphins. Low endorphin levels result in increased TNFα and IL-6. So not only does chronic pain magnify obesity by four different mechanisms, it magnifies the toxicity of the obesity as well.

Substance Abuse

We have already talked about the effects of marijuana in blocking leptin through the cannabinoid receptor so we won’t talk more about why pot gives potheads the munchies. But there are other substances that are abused, some legal, and some illegal, that contribute to either obesity or the toxicity of obesity that should be discussed. The first of these is tobacco.

This can’t be right you say. Everyone knows that stopping smoking causes weight gain, and there right. Here’s how it works. Nicotine binds to the cells in the arcuate nucleus and enhances the effects of leptin. This slows down appetite and increases metabolic rate. Studies on rimonabant, the cannabinoid blocker, show it can be effective in reducing the cravings from nicotine withdrawal so it is possible the effect of nicotine on leptin is via this mechanism. So we should all smoke right? Not so fast. Remember it’s not the obesity that kills you; it’s the toxic effect of the obesity that kills you. So what effect does tobacco have on the central actors in obesity toxicity, TNFα and IL-6?

Well we know a lot about the way this works. Nicotine from the tobacco enters the body. It binds to special nicotine receptors called nicotinic acetylcholine receptors (nAChRs) which cause the release of a free radical called peroxynitrite. The peroxynitrite travels through the blood to the fat cells where it turns on the nuclear factor kappa B (NF-κB). NF-κB then starts producing TNFα and IL-6. This whole model was confirmed in a study that shows the effects can even be caused by second hand smoke. So while smoking cigarettes won’t make you gain weight, it will make the fat you have more toxic to the body and it’s fat’s toxicity that kills you. So stop smoking.

What else causes an increase in TNFα production? Methamphetamine. Not only does methamphetamine cause an increase in TNFα but in a truly vicious cycle, the TNFα reduces the ability of methamphetamine to raise dopamine levels in the brain. In more simple terms, using methamphetamine increases the toxicity of fat just like smoking does. But that toxicity in turn decreases the euphoric effect of the met requiring met users to need more met with time to get the same euphoric feeling. The scary thing is this effect was seen with only 5 doses of methamphetamine.

So what else increases TNFα and IL-6 production? Chronic alcohol abuse. Modest consumption of alcohol leads to a decrease in TNFα and IL-6. But in a study of alcoholics, levels of TNFα were 70% higher and IL-6 levels were 50% higher in chronic alcoholics than they were in non-alcoholics. So while chronic alcoholics typically lose weight and have less body fat, the fat they do have is more toxic because of the alcohol abuse.