Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 1 • January 2013

Leptin and Weight Control Leptin Resistance Increased Under Inflammatory Conditions

In the October 2012 issue of this newsletter, we wrote about the strong relationship between increased levels of the hormone leptin, secreted primarily by adipocytes (fat cells), and increased body fat. Leptin levels are known to be elevated in obese individuals. This elevation is now thought to be associated with leptin resistance, the failure of leptin signaling to properly regulate energy balance by acting as a negative feedback adiposity signal, decreasing food intake and increasing energy expenditure. In an apparent attempt at compensation for the leptin resistance, more leptin is secreted.

Leptin resistance is increased under proinflammatory conditions, such as the low-grade inflammation of obesity and diabetes. A fairly recent paper1 reported that leptin resistance was induced through direct interaction with the proinflammatory C-reactive protein (CRP). The researchers found that “CRP not only binds to plasma leptin but also impairs leptin signaling and attenuates its physiological effects in vivo.”1 “We also report here a stimulatory effect of physiological concentrations of leptin on the hepatic [liver] expression [in mice] of human CRP. This finding is consistent with recent reports that human plasma CRP concentration is independently correlated with leptin concentration.”1

Leptin resistance is also induced by a high fat diet via two independent causes: “an apparent defect in access to sites of action in the hypothalamus that markedly limits the ability of peripheral leptin to activate hypothalamic STAT signaling, and an intracellular signaling defect in leptin-responsive hypothalamic neurons that lies upstream of STAT3 activation.”1b

Aged rats are reported to have increased fat mass, central leptin and insulin resistance, and hyperleptinemia. The consequences of leptin resistance are failure to inhibit food intake, deplete fat stores, down regulate its own expression in adipose (fat) tissue, and increase energy expenditure.1c A current hypothesis suggests that “during aging, progressively elevated levels of leptin result in an activation of sympathetic nervous system (SNS) that brings about its desensitization, thus at advanced ages leptin fails to increment energy expenditure.”1c

Increasing Leptin Transport Into the Brain

In order for leptin signaling to reach brain areas controlling feeding and body temperature, it must pass through the blood-brain barrier. Indirect evidence suggests that in obesity there is impaired transport of leptin across the blood-brain barrier (BBB).2 Direct evidence is provided by a study which showed that obese outbred mice transport leptin into the brain less rapidly than lean mice, while two other studies were cited that found reduced leptin transport in inbred strains of obese rats, including Koletsky and Zucker (papers cited in reference #2). The paper2 reported that leptin transport across the BBB was enhanced by alpha1-adrenergic agents, such as epinephrine (adrenaline). Ephedrine also worked. Tyrosine, an amino acid precursor of catecholamines (including adrenaline) was also a potent stimulator of the leptin transporter at the BBB and was the only amino acid tested that did so.

The author notes a caveat: if adrenaline levels are maintained at chronic high concentrations, there can be a desensitization in the ability of adrenaline to suppress leptin levels.

A later paper by the author of paper #2,2b notes that serum levels of leptin are elevated more than in the CSF (cerebrospinal fluid), additional evidence that the transport of leptin across the BBB is inhibited. Indeed, obese rodents are reported to respond to leptin delivered directly into the brain but not to leptin given peripherally.2b The paper also reports that “[s]everal labs have now examined transport rates [of leptin] in obese rodents. In several cases, the transport rate is dramatically reduced.”2b Finally, the author notes that leptin transport shows a diurnal rhythm and is affected by sex steroids, insulin, glucose, and epinephrine (adrenaline).2b

Another paper3 reported that green tea extract protected leptin-deficient ob/ob obese mice from fatty liver. Leptin deficiency resembles leptin resistance even with high leptin levels. The mechanism(s) by which green tea extract significantly reduced liver lipids and triglycerides along with improved liver function in these leptin-deficient obese mice was, however, unclear. A number of possible mechanisms were described. ob/ob mice were reported in a study cited in paper #3 to have decreased norepinephrine that inhibits adipocyte lipolysis and favors lipid storage. However, not mentioned was the possibility that reduced sympathetic nervous system activity may reduce the transport of leptin to the brain across the BBB. ob/ob mice treated with norepinephrine have also been reported to have decreased pro-inflammatory cytokines.3


1. Chen et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med 12(4):425-32 (2006).
1b. El-Haschimi et al. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 105(12):1827-32 (2000).
1c. Carrascosa et al. Changes in the neuroendocrine control of energy homeostasis by adiposity signals during aging. Exp Gerontol 44:20-5 (2009).
2. Banks. Enhanced leptin transport across the blood-brain barrier by alpha-1-adrenergic agents. Brain Res 899:209-17 (2001).
2b. Banks. Is obesity a disease of the blood-brain barrier? Physiological, pathological, and evolutionary considerations. Curr Pharm Des 9:801-9 (2003).
3. Bruno et al. Green tea extract protects leptin-deficient spontaneously obese mice from hepatic steatosis and injury. J Nutr 138:323-31 (2008).

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