Obesity and Weight Loss
- Restore insulin sensitivity
- Restore youthful hormone balance
- Control rate of carbohydrate absorption
- Increase physical activity
- Restore Brain Serotonin/ Suppress Hunger Signals
- Restore resting energy expenditure rate
- Restore healthy adipocyte (fat cell) signaling
- Inhibit the lipase enzyme
- Eat to live a long and healthy life
This protocol will detail the biological underpinnings of obesity and weight gain. Consideration will be given to each pillar of successful weight loss in the context of obesity risk factors in order to highlight the inadequacies of typical weight loss strategies. Methods of utilizing novel natural compounds and strategically incorporating some pharmaceutical options to support critical metabolic factors for long-term weight management will be discussed.
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 stomach tissue can directly signal satiety 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 released at various levels of the gastrointestinal tract perform numerous functions in the balance of energy intake and utilization. Insulin (released from the pancreas and critical for the uptake of glucose into cells) and cholecystokinin (CCK) (secreted by the upper part of the small intestine and important for 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 the hormone leptin (Marieb 2010). Leptin is secreted into the blood by adipose (fat) cells in proportion to their levels 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 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 leptin levels. This leads to down regulation of cellular sensitivity to the effects of leptin, a physiologic state known as leptin resistance. Weight loss efforts put forth by obese individuals may be undermined by failure of the leptin system to suppress their appetite, resulting in excessive 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 thus represents 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
Weight gain and progression to obesity can be caused by energy imbalances (Hill 2012). 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 (Mårin 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