Regulation of Body Weight

Our system of energy balance evolved to ensure that a healthy person maintained adequate reserves of body fat to sustain life through repeated times of food scarcity, including famine. Food energy abundance is a relatively recent phenomenon, quite dissimilar to the vast majority of time over the past 100 000 years. In fact, body weight maintenance is achieved by the very complex and interrelated interaction of neurological and hormonal factors, with the goal of increasing appetite and preserving body fat when energy stores are low.

 Within the brain, a region called the  hypothalamus  monitors and integrates neurological signals and modulates appetite accordingly. Sensory cells located within the stomach walls that detect stretching of the stomach can directly signal to the brain through nerve impulses. Indirectly, blood levels of glucose, fatty acids, and amino acids (components of proteins) stimulate the perception of satiety in brain centers and depress eating behavior. Additionally, a variety of hormones are released at various levels of the gastrointestinal tract to perform a number of functions in the balance of energy intake and utilization. Insulin  (released from the pancreas and critical to the uptake of glucose into cells) and  cholecystokinin (CCK) (secreted by the upper part of the small intestine and important for the triggering release of digestive enzymes and bile) are also potent satiety signals (Marieb 2010).  

In addition,  fat stores  in the body are able to relay the overall state of energy storage to the brain through the secretion of leptin hormones.  (Marieb 2010). Leptin is secreted into the blood by adipose (fat) cells in proportion to their level of stored fats. It travels to the brain and acts upon the hypothalamus, stimulating the release of neurotransmitters that signal satiety, and suppressing those that signal the hunger. Thus, leptin released by adipose tissue provides the brain with information on long-term energy economy, and allows it to adjust food intake accordingly (Begg 2012). However, this intricate system of appetite control can become perturbed in obesity, as excess fat stores contribute to chronically elevated levels of leptin. This leads to down regulation of cellular sensitivity to the effects of leptin, and physiologic state known as  leptin resistance . Weight loss efforts put forth by obese individuals may be undermined by the failure of the leptin system to suppress their appetite, resulting in an excess of hunger (Myers 2010).  

Another hormone derived from fat cells, called  adiponectin , is an  anti-obesity  signaling molecule; Adiponectin signaling is disrupted in obesity-related diseases and states of insulin resistance (Shehzad 2012). Evidence suggests that leptin and adiponectin can work together to combat insulin resistance (Yamauchi 2001; Kadowaki 2011; Siasos 2012). Optimizing fat cell signaling, as  an important aspect of any comprehensive weight loss strategy.

Resting energy expenditure (REE) also influences weight gain and progression to obesity. REE is the rate at which metabolic activity burns calories during periods of rest or inactivity. Having a low REE may contribute to weight gain or make it difficult to lose weight. Studies show that REE is directly related to serum adiponectin levels, and that higher leptin levels (as occurs in leptin resistance; see below) are associated with decreased REE (Brusik 2012). Aging is also associated with decreased REE (Hunter 2001; Bosy-Westphal 2003). These findings suggest that boosting REE could be a valuable strategy to mitigate age-related weight gain.

Causes and Risk Factors for Obesity

Aging can negatively affect the balance of energy input and expenditure in several ways. The natural aging process is associated with hormonal changes, particularly decreases in sex and thyroid hormones, which contribute to a decrease in metabolism and energy expenditure. Advancing age is also associated with reduced insulin sensitivity, which may interfere with appetite control (Begg 2012; Paolisso 1999). With age also comes a decrease in physical activity, which further reduces energy expenditure. Only about a quarter of Americans aged 65 to 74 exercise daily; this drops to less than 1 in 10 at age 85 (AoA Statistics 2008). Obesity and decreased mobility in the aging individual may have reciprocal effects on one another; age-related increases in weight and reductions in muscle mass lead to decreased mobility and energy expenditure. In a review of 28 population studies of older obese individuals, all but one showed significant associations between obesity and reduced mobility (Vincent 2010).

Sex Hormone and Thyroid Hormone Insufficiencies/ Imbalances

Levels of sex hormones (such as testosterone and dehydroepiandrosterone [DHEA]) decline with age in both genders. This may lead to an increase in fat mass, reduction in lean body mass or central fat redistribution (Apostolopoulou 2012; Villareal 2004). Similarly, declining thyroid hormone levels are associated with reduced metabolic rate and thus obesity (Biondi 2010).

In men, free testosterone levels sharply declines between the ages of 40 and 80. Both free and total testosterone levels are significantly lower in overweight and obese men compared to those with weights in a normal range across all ages (Wu 2008). Men with low testosterone levels (hypogonadism) develop increased fat mass, and testosterone replacement therapy in hypogonadal men reduced fat mass by 6% in one study (M?rin 1995; Kaufman 2005).

Obesity and low testosterone have a complex relationship; low testosterone can be considered both a cause and consequence of obesity (Wu 2008). In men, increases in fat mass may also increase the conversion of testosterone to estrogen by the enzyme aromatase (Vermeulen 2002). While this conversion is a normal phenomenon, aromatization occurs more readily in fat tissue, and is increased by obesity, age, inflammation, insulin, leptin, and stress (Williams 2012). Thus, in older men with excessive abdominal fat, the ratios of testosterone to estrogen are lower than in younger men. Elevated estrogens, similar to low testosterone levels, are associated with increased abdominal fat (Vermeulen 2002). If a blood test reveals elevated estrogen (estradiol) levels in a man, a physician may prescribe an aromatase-inhibiting drug such as anastrozole (Arimidex?).

In women, estrogen levels decline suddenly with menopause. Hormone replacement has shown modest increases in lean body mass and reductions in waist circumference and abdominal fat in some, but not all studies of post-menopausal women (Salpeter 2006; Mayes 2004; Norman 2000).

The thyroid is a central regulator of metabolism; it integrates signals from the brain and secretes thyroid hormone (thyroxine or T4) to influence metabolism in a variety of tissues (Biondi 2010). Thyroid dysfunction can affect body weight and composition, body temperature, and energy expenditure independent of physical activity. Depressed thyroid function (hypothyroidism) has been associated with decreased thermogenesis (conversion of stored energy into heat) and metabolic rate, and weight gain (Biondi 2010).

Clinical studies have shown that treatment of hypothyroidism with thyroxine may lead to weight loss, and population studies suggest that low T4 levels and high TSH levels are both associated with higher BMI (Asvold 2009). Depressed thyroid activity is also more common as people age; hypothyroidism in the general population is 3.7%, but is 5 times more common in individuals aged 80 or older when compared to 12 to 49 year-olds (Aoki 2007).

A significant number of patients with morbid obesity display elevated thyroid stimulating hormone (TSH) levels. TSH is produced in the brain by the pituitary gland, then travels to the thyroid and stimulates the production of thyroid hormone. Increased blood levels of TSH may indicate thyroid dysfunction and are associated with the progression of obesity (Rotondi 2011). For example, in one Norwegian study of over 27 000 individuals older than 40, TSH correlated with BMI: for every unit that TSH increased, BMI increased by 0.41 in women and 0.48 in men (Asvold 2009). 

Insulin Resistance and/or Leptin Resistance

In addition to being a result of obesity, elevated levels of the hormones leptin and insulin in obese individuals may be indicative of a resistance to their activities. Insulin is a hormone that helps facilitate cellular uptake of glucose, primarily in the muscles, liver, and adipose tissue. When insulin resistance develops, glucose levels are no longer efficiently controlled by the action of insulin and blood levels become elevated, predisposing the insulin-resistant individual to several chronic diseases associated with aging (NDIC 2011). Moreover, while higher levels of both leptin and insulin normally suppress the desire to eat and stimulate energy expenditure, they are unable to perform this function in resistant individuals (Hagobian 2010).

• Insulin resistance is a consequence of sustained hyperinsulinemia (high insulin levels) and is complicated by chronic inflammation and obesity (Sung 2011; Ortega Martinez de Victoria 2009; Weisberg 2003). Strategies aimed at improving insulin sensitivity are an integral part of the nine pillars of successful weight loss. These strategies can include use of a low-cost prescription drug called metformin, which is approved for the treatment of type 2 diabetes and can also help reduce body fat, and natural compounds that help promote healthy insulin signaling (see below) (Despres 2003; Berstein 2012).
• Similarly, leptin resistance results from sustained periods of high leptin secretion associated with high fat stores. In obese individuals, leptin may lose its ability to be transported into the brain (Jéquier 2002). An interaction between leptin and the inflammatory biomarker C-reactive protein (CRP) in cell culture suggests a role of chronic inflammation in leptin resistance and the loss of appetite control. In an animal model of obesity, infusions of CRP countered the appetite-suppressing effects of leptin. The scientists who conducted these experiments postulated that CRP may bind to leptin and inhibit its physiologic functions (Chen 2006). Based upon these findings, interventions that ease inflammation, such as the plant compound curcumin and omega-3 fatty acids from fish oil, may help combat the detrimental effects of leptin resistance (Yu 2008; Shao 2012; Selenscig 2010; Tsitouras 2008). In addition, the mango-like fruit of Irvingia gabonensis, a tree found in Africa, has also been shown to combat leptin resistance and lower CRP levels (Ngondi 2009; Oben 2008).

Overeating and Dining Out

Increases in daily average food consumption significantly contribute to weight gain in the United States (Swinburn 2009). Data from the National Health and Nutrition Examination Survey (NHANES) show a significant increase in average daily energy intake between 1971 and 2000, amounting to 168 calories per day for men, and 335 calories per day for women. Without increased expenditure, this represents potential theoretical weight gains of 18 pounds per year for men and 35 pounds per year for women (Hill 2012). A separate study estimates a 350 calorie per day increase for children (about one can of soda and a small order of French fries) and a 500 calorie per day increase for adults (about one large hamburger) over our daily calorie intake in the 1970s (Swinburn 2009).

Eating outside of the home can encourage overconsumption, especially of calorie-dense, nutrient-poor foods. Spending on food away from home has almost doubled in the last half century, rising to almost one-third of a person’s calories in the United States (Cohen 2012). Half of Americans eat out 2 or more times per week, and 20% of males and 10% of females eat commercially prepared foods 6 or more times per week (Kant 2004).

People have a decreased ability to make healthy food choices away from home for several reasons. They tend to increase their consumption proportional to the amount of food they are served, and average portion sizes have been steadily increasing over the last 30 years (Rolls 2006; Nielsen 2003). Choices for foods consumed away from home are also influenced by marketing, and the relative abundance of high-calorie, low-nutrient choices compared to healthier ones. Fast food restaurants may also play into inherent weaknesses in human cognitive capacity. Reasoned decisions are time-consuming; therefore, people often depend on automatic choices when they are hungry. When glucose levels are low, or a person is distracted or preoccupied, they tend to make less healthy food choices and are often unaware of the quality of food they have consumed. Although attempts have been made to provide point-of-sale nutritional labeling in many restaurants, there has been limited evidence of effect (Cohen 2012).

In an effort to avoid the caloric excess to which so many restaurant-goers succumb, suppression of hunger signals is likely to be of great benefit. To this end, several natural compounds, including saffron extract, L-tryptophan, and pine nut oil, as well as the pharmaceutical drug lorcaserin (Belviq?) may be of benefit; each of these compounds is discussed in detail later in this protocol.

Another strategy to counter the excessive amount of calories encountered when dining out involves “preparing your body to eat” by taking measures to reduce the rate at which fats and carbohydrates are absorbed. Supplementing with green coffee extract before meals can slow carbohydrate absorption, helping to reduce after-meal spikes in glucose levels (Vinson 2012). These after-meal glucose spikes inflict damage to cells via multiple mechanisms and have been linked to cardiovascular disease, cancer, Alzheimer’s disease, and kidney failure. Also, a pharmaceutical drug called orlistat (Alli?, Xenical?) can help reduce the absorption of fats by inhibiting an enzyme called lipase (see below) (McClendon 2009; Smith 2012). Targeting after-meal spikes in blood levels of glucose (postprandial glycemia) and fatty acids (postprandial lipemia) is a critical step towards averting cardiovascular disease, for which obesity is a leading risk factor (Blaak 2012; Strojek 2007; Sahade 2012; Jackson 2012).

Altered Serotonin Signaling, Chronic Stress, and Appetite

Low levels of the neurotransmitter serotonin, typically associated with depression, may be associated with weight gain. Serotonin interacts with receptors in the brain that regulate feeding behavior (Sargent 2009). When brain levels of serotonin are increased, the desire to eat is decreased; as serotonin levels drop, appetite is stimulated (Lam 2010). Mimicking the serotonin-receptor interaction has been the target of several anti-obesity drugs developed over the last 4 decades (Ioannides-Demos 2011). Moreover, studies have shown that obese individuals have low levels of tryptophan, a precursor to serotonin, in their blood (Breum 2003). These findings suggest that restoring serotonin signaling may be a way to combat hunger cravings that can preclude weight loss.

While stress is an important adaptation essential for survival, long-term stress can be damaging. Chronic stress can compromise the function of hormonal, gastrointestinal, and immune systems (De Vriendt 2009). Exposure to chronic stress has been associated with obesity and metabolic syndrome in human and animal studies (Müssig 2010). Stress increases production of the hormone cortisol, which when combined with access to abundant food, promotes the development of visceral obesity (Bj?rntorp 1991).

Cortisol promotes weight gain in several ways. Visceral fat tissue contains a high number of cortisol receptors and responds to circulating cortisol by increasing fat cell growth and lipid storage (Fried 1993). Cortisol may also stimulate the neurotransmitters that signal hunger and decrease the activity of leptin, which signals satiety (Bj?rntorp 2001). Activation of the stress response appears to stimulate the human appetite for highly palatable, energy-dense foods (Torres 2007), which may explain the association between emotional stress and increased food intake (Müssig 2010). 

Important Obesity-Related Tests

 Knowledge of one’s overall risk enables the selection of an appropriate weight loss strategy. For example, sufficient levels of thyroid hormone are necessary to minimize obesity risk; thyroid insufficiency can be treated with hormone replacement. Low levels of testosterone and estrogen are associated with weight gain in men and women, respectively, and sufficient DHEA is essential for sex hormone production. High cholesterol, high blood pressure, and chronic inflammation are all risk factors for one or more of the obesity-related diseases.