Insulin Resistance Labs – Leptin

History of Leptin

Leptin was discovered in 1994 when Friedman and colleagues performed positional cloning of the ob gene, responsible for a recessive mutation found decades earlier to cause obesity in the homozygous ob /ob mouse.1 The researchers discovered that this gene encodes a secreted peptide hormone, expressed almost exclusively in adipose tissue, which they named “leptin.”

Deficiency of leptin in the homozygous ob /ob mice causes morbid obesity, severe insulin resistance, hyperglycemia, hyperphagia (uncontrolled eating behavior), decreased energy expenditure, lethargy, central hypothyroidism, and other neuroendocrine abnormalities.1,2 Treatment of ob /ob mice with purified leptin reduces food intake, normalizes insulin-glucose homeostasis, increases energy expenditure, and reduces body weight.3,4

Leptin acts primarily on the hypothalamus to induce metabolic changes in brown adipose tissue and skeletal muscle via the sympathetic nervous system; specifically, leptin enhances mitochondrial function and induces the mitochondrial uncoupling protein UCP1 in these tissues, producing an enormous increase in energy expenditure via thermogenesis (body heat production).5 Because lipids (fatty acids in particular) are the primary fuel substrate for mitochondrial thermogenesis, leptin treatment also reverses the pathological accumulation of lipid (i.e., lipotoxicity) that causes insulin resistance and glucose intolerance in ob /ob mice.6 The net effect of these changes is rapid weight reduction and normalization of insulin-glucose homeostasis in leptin-treated ob /ob mice.3

Identification of the human leptin gene (OB or LEP ) in 1995 opened the possibility of using leptin to treat human obesity, insulin resistance, and diabetes.7 This possibility was confirmed in part with the discovery of individuals with recessive loss-of-function mutations in the human leptin gene. These mutations are extremely rare, with only a handful of affected families discovered worldwide in the past decade.8 Analogous to the ob/ob mice, a leptin deficient individual has no detectable circulating leptin and is obese, hyperphagic, and severely insulin-resistant from early childhood. Treatment with recombinant human leptin reverses all of these defects and normalizes metabolism in these individuals in a matter of weeks.9

Leptin has also been found to be effective in reducing metabolic abnormalities in individuals who lack normal adipose tissue depots due to congenital or acquired generalized lipodystrophies.10,11 Unlike individuals with genetic leptin deficiency, lipodystrophic individuals are exceedingly lean and produce little or no leptin due to the lack normal adipose tissue (where leptin is normally produced).12 Lipodystrophic individuals adapt to the inability to store lipids in fat by inappropriately storing them in other tissues such as muscle and liver, resulting in severe lipotoxic insulin resistance, diabetes, and eventually fulminant liver failure due to steatohepatitis.13 Leptin treatment of lipodystrophic individuals reverses or ameliorates these metabolic derangements.

Despite these examples of beneficial effects of leptin treatment, studies with purified recombinant human leptin in common types of obesity were disappointing: most individuals with obesity exhibit little or no change in weight with leptin treatment.14,15 Why is this?

Leptin regulates feeding behavior and metabolism

The brain (hypothalamus) receives information from “adiposity signals” such as the hormones insulin and leptin (reflecting long-term energy availability) and signals from nutrients such as glucose and free fatty acids (reflecting short-term energy availability).16,17

When there is sufficient access to food and body fat stores are ample, feeding behavior and metabolism should be adjusted to decrease energy intake (enhance the sense of satiety) and endogenous glucose production, while simultaneously increasing energy expenditure and mobilizing fat stores.18

On the other hand, if the brain has decreased signal input from these “adiposity signals” then the brain adjusts metabolism to increase nutrients in the blood stream. In part, this is accomplished by increasing glucose production (gluconeogenesis) in the liver.19 With the consequent rise in body fat content and blood glucose levels, blood levels of leptin, insulin, and free fatty acids also increase, providing negative feedback to the brain and restoring food intake and glucose production to their former values.15

Leptin production is directly coupled to fat mass, obese people generally exhibit unusually high circulating levels of leptin that are sustained over many years. This chronic elevation of leptin in obesity, along with hyperinsulinemia and other metabolic derangements, are believed to produce a state of “leptin resistance” in the hypothalamus.16 In effect, the primary pathway through which leptin controls appetite and metabolism becomes inherently flawed at some point in obese individuals, such that the brain does not adequately receive or relay the signal to decrease food intake and increase energy expenditure.

Leptin:BMI Ratio

It is now recognized that leptin resistance may be variable among obese individuals. Calculation of the plasma leptin:body mass index (BMI) ratio (i.e., a “BMI-adjusted” leptin level) is one way to quantify severity of leptin resistance in obese individuals.20

Leptin:BMI ratios vary substantially among obese individuals, because circulating leptin levels reflect both total adipose tissue mass (estimated by BMI) and the severity of hypothalamic leptin resistance. Sympathetic enervation of adipose tissue and circulating catecholamines normally suppress production and release of leptin by adipose tissue.21,22

Leptin resistance in the hypothalamus and the subsequent decreased sympathetic outflow to fat produces even greater production and release of leptin (further aggravating hypothalamic leptin resistance in a feed-forward manner). Therefore, if circulating leptin levels are in excess to fat mass (estimated by BMI), it is indicative of a more severe state of leptin resistance. The leptin:BMI ratio provides a quantitative assessment for the severity of leptin resistance in obesity.

For the same age and BMI, women have significantly higher leptin concentrations than men (mean levels: women 14.13 pg/mL vs. men 5.73 pg/mL).23

Leptin risk ranges are:

• High risk: > 43 ng/mL
• Intermediate risk: 20–43 ng/mL
• Optimal: < 20 ng/mL

The risk ranges for the Leptin:BMI ratio are:

• High-risk: > 1.17
• Intermediate risk: 0.66–1.17
• Optimal: < 0.66

Clinical Interpretation

While absolute leptin deficiency causes obesity, most obese individuals exhibit elevated circulating plasma leptin levels—as would be expected, given that leptin is synthesized and secreted by adipocytes in direct proportion to total body fat mass.16

Leptin resistance

Sustained elevations in plasma leptin levels are associated with obesity, overeating, and inflammation-related diseases including hypertension, metabolic syndrome, and cardiovascular disease (CVD).24 It is thought that increases in leptin level (in response to caloric intake) act as an acute response mechanism to prevent excess cellular stress caused by over-eating when adipose tissue depots are already replete, which can lead to ectopic fat storage within internal organs, arteries, and muscle.25 In other words, Leptin is trying to keep you from over-eating.

The postprandial rise in circulating insulin levels induces an increase in leptin in a dose-dependent fashion. This effect is enhanced by high cortisol levels.26 However, although most obese individuals have high leptin levels, these common forms of obesity are associated with acquired impairment in the response to elevated leptin levels, which therefore do not induce the expected reduction in feeding and body weight that would mitigate obesity.

Furthermore, although recombinant leptin can be used to treat the rare monogenic form of leptin deficiency and the generalized lipodystrophies, administering the hormone to obese individuals does not always induce weight loss as predicted, suggesting that they may be resistant to the effects of leptin.27

Such “leptin resistance” is thought to be an important component in the development of obesity and is somewhat analogous to “insulin resistance,” wherein elevated insulin levels are required to maintain blood glucose levels in the normal range.27,28 The chronic hyperleptinemia which characterizes obesity decreases the transport of leptin into the central nervous system (CNS) and/or impairs the signaling properties of leptin receptors such that acute leptin responses do not adequately signal “fullness” to the brain to curb hunger.

This confers increased susceptibility to diet-induced obesity, which in turn raises leptin levels further and worsens leptin resistance, leading to a vicious cycle of weight gain. Therefore in addition to being a major cause of obesity, leptin resistance is also an important consequence.28-30

Leptin controls feeding not just by providing a physiological satiety signal, but also by modulating the perception of reward associated with feeding.30 This action of leptin probably occurs at the level of the mesolimbic dopaminergic system, and may explain the weight gain commonly induced by antipsychotic drugs, which act as mixed dopamine receptor antagonists.31

Based on existing knowledge, obese individuals with more severe leptin resistance are likely to struggle more with dieting and weight loss through lifestyle interventions and may experience rebound of weight gain more quickly after weight loss; in addition, these individuals may exhibit more severe insulin resistance along with an increased number and severity of components of the metabolic syndrome (e.g., hyperglycemia, central adiposity, hypertension, hypertriglyceridemia, and reduced HDL-cholesterol).17

Since production of adiponectin by adipose tissue is generally suppressed by worsening insulin resistance, the leptin:adiponectin ratio may be useful in assessing the synergistic metabolic impairment caused by insulin resistance and leptin resistance in a given individual. Consistent with this, several recent studies have demonstrated that the leptin:adiponectin ratio is a novel, independent predictor of type 2 diabetes (T2DM) and CVD.32-35

Leptin affects glucose metabolism and insulin sensitivity in peripheral tissues

Outside of the Central Nervous System, leptin can directly affect glucose metabolism by enhancing insulin action in the skeletal muscle, liver, adipose tissue, and by improving function of the pancreatic β cells.36 Leptin suppresses insulin secretion from the pancreas, decreases the production of glucose in the liver, and increases glucose and fatty acid oxidation in both muscle and adipose tissue.36,37 Most of the effects of leptin are mediated on these tissues indirectly via leptin actions in the hypothalamus.

Consistent with this, epidemiologic data show a strong association between insulin resistance and the chronically increased leptin levels associated with leptin resistance (reviewed in 38). The hyperinsulinemia ensuing from insulin resistance plus loss of the protective effects of leptin action can augment the exhaustion and apoptosis of pancreatic β cells, eventually resulting in T2DM.39,40 Pancreatic β cells have leptin receptors and leptin may also be an important direct regulator of β-cell function at different levels including insulin gene expression, insulin secretion, cell growth, and apoptosis.36,38

Although leptin treatment reduces insulin levels and enhances insulin sensitivity in various hypoleptinemic states (primarily by decreasing body weight and fat mass),41 it does not improve insulin sensitivity in obese individuals or those with T2DM for whom leptin excess is associated with leptin resistance.38,42

Leptin and inflammation

A link exists between obesity and chronic inflammation, and it has been proposed that leptin regulates some aspects of the inflammatory response. Leptin production is acutely increased during infection and inflammation.43,44 Elevated leptin also affects the hypothalamic-pituitary-adrenal (HPA) axis and is associated with raised white blood cell counts, indicating a role in the physiological stress response.45,46

Factors that influence inflammatory markers in general can acutely affect leptin levels. In such situations leptin may no longer strictly correlate with body fat mass:43,44

• Leptin levels decrease after short-term fasting (24–72 hour), even when body fat mass does not.47
• Leptin levels are elevated in obese patients with obstructive sleep apnea, but decrease after CPAP treatment.48
• Sleep deprivation reduces leptin levels (leptin is released into the circulation in a pulsatile fashion, following a circadian rhythm, and hence is affected by sleep patterns).49,50 However, sleep disturbances have been shown to increase leptin levels in women of normal weight who have depressed mood.51
• Chronic exercise training decreases leptin levels.52
• Perceived emotional stress reduces leptin levels.53
• Leptin levels are decreased by testosterone and increased by estrogen.54
• Renal failure results in higher leptin levels.55 Leptin levels may be higher in women at the luteal phase of the menstrual cycle, and menopause is associated with a decline in circulating leptin.56,57

Leptin and cardiovascular disease

The relationship between leptin and CVD is complex.58-60 Leptin is necessary for normal cardiac function, as it plays a critical role in preventing cardiac lipotoxicity (lipid accumulation) in obesity.61

In animal models of leptin deficiency, leptin treatment also reduces cellular damage via suppression of cardiomyocyte apoptosis in animal models of ischemia reperfusion injury.62 However, leptin deficiency in animals is distinctly different from the phenomena of leptin resistance and hyperleptinemia that typify normal human obesity.

Hyperleptinemia is present in patients with coronary heart disease, chronic heart failure, hypertension, stroke, and in those at increased risk of myocardial infarction (MI).42,58,59,63 Hyperleptinemia may play a direct role in the pathogenesis of CVD by inducting platelet activation, smooth muscle cell proliferation, endothelial dysfunction, and oxidative stress.64

Consistent with these pro-atherogenic effects, elevated plasma leptin concentrations are independently associated with carotid intimal-medial thickness (CIMT) and with coronary artery calcification score in patients with T2DM, even after controlling for adiposity.60

These pro-atherogenic effects of leptin have obvious negative implications for obese individuals exhibiting leptin resistance. Nevertheless, the complex association between leptin and cardiac function may be one factor underlying the so-called “obesity paradox”; i.e., the observation that survival from certain CVD-related endpoints may be paradoxically increased in individuals with increased BMI.”65

Treatment

To date, several interventional studies have been performed to evaluate the effects and safety of leptin administration in lipoatrophic or obese patients with hypoleptinemia. Administering recombinant human leptin can reverse the obesity of leptin-deficient (but NOT leptin-resistant) individuals and corrects many of the associated metabolic abnormalities including diabetes, dyslipidemia, and hepatic steatosis.66-68

Clinical trials are ongoing to find a modified, more potent therapeutic with a longer half-life, to reduce the frequency of injections and accompanying skin inflammation.69-71 Leptin replacement to children with congenital leptin deficiency remarkably ameliorates hyperinsulinemia and hyperlipidemia.72 Recent randomized trials demonstrate that combination treatment with an amylin analog and human recombinant leptin significantly decreases not only body weight but also insulin levels in obese subjects.73

Importantly, individuals with evidence of more severe leptin resistance will likely require greater medical and social support measures to achieve and maintain substantial weight loss through lifestyle modifications such as diet and exercise. Hence, these individuals may benefit from more frequent and intensive interaction with medical providers, dieticians, and nutrition and exercise counselors to successfully lose weight and maintain weight loss.

In addition, bariatric surgery may be a consideration in the treatment of obese individuals with leptin resistance, especially for individuals with type 2 diabetes or other obesity-related morbidities recognized as indications for bariatric surgery.

In general, for obese individuals with elevated circulating leptin levels, weight loss may be one of the primary therapeutic targets. The following lifestyle recommendations and medications can be used to reduce insulin resistance and improve β-cell function, personalized to the individual patient’s clinical needs.

Lifestyle74-80 :

• Limit carbohydrates (especially simple sugars and processed carbohydrates) while maintaining moderate fat intake
• Weight loss (as appropriate)
• Regular exercise (150 minutes/week combining cardiovascular activity at a moderate-to-vigorous pace with resistance training)

Medication choices may include:

• Metformin (e.g., Glucophage®, Glumetza®)
• Pioglitazone (Actos®)
• Incretin mimetics (GLP-1 agonists)
• DPP-4 inhibitors
• Quick-release bromocriptine mesylate (Cycloset®)
• Alpha-glucosidase inhibitors (acarbose)
• Leptin Manager (supplement from Xymogen) – shown to reduce weight (0.55kg loss in 12 wks) and leptin levels.

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