C-Reactive Protein May Induce Leptin Resistance

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 9 No. 3 • August 2006

C-Reactive Protein May Induce Leptin Resistance

The hormone leptin, secreted by adipocytes (fat cells), has numerous effects, including, among others, immune system regulation, regulation of the reproductive system, and acting as a nutrient signal in the hypothalamus that helps regulate food intake. In normal-weight individuals, increases in leptin signaling decrease food intake. In leptin-deficient animals and humans, treatment with leptin has a profound normalizing effect upon food intake and weight. Obese humans, however, have increased levels of leptin rather than leptin deficiency, and leptin treatment has proven ineffective in decreasing food intake and, hence, body weight. This “leptin resistance” has been extensively studied to determine how obesity decreases the effects of leptin signaling.

Authors of a very recent paper1 propose that leptin resistance may be “partially attributed to interactions between leptin and plasma circulating factors.” They suggest that such factors might bind leptin to affect its transport or otherwise inhibit its effects. They note that “elevation of the protein suppressor of cytokine signaling-3 (SOCS-3), which is induced by leptin, might diminish the actions of leptin in the central nervous system.”

They now identify C-reactive protein (CRP), a marker of inflammation found in the bloodstream and a risk factor for cardiovascular disease, as a blood-borne substance that not only “binds to plasma leptin but also impairs leptin signaling and attenuates its: physiological effects in vivo.” Moreover, they report, “leptin directly stimulates expression of CRP in human primary hepatocytes [liver cells] in vitro.” In their experiments, the researchers found that the concentration of human CRP and rat CRP required to block one of leptin’s effects (phosphorylation of STAT3) were within the ranges observed in rat and human plasma. They also found that human CRP inhibited human leptin signaling in the leptin-triggered JAK-STAT and PI3K pathways in rat primary hypothalamic neurons. In the ob/ob (genetically obese) mouse studies, human leptin produced the expected reduction in food intake and body weight. However, when coadministered with human CRP, the result was a partially attenuated effect of leptin (at low CRP dose) or a completely blocked leptin effect (at high CRP dose). CRP alone had no effect on food intake or body weight.

Chronically elevated CRP (a state of chronic inflammation) has also been found to be positively correlated with adiposity (as well as with leptin levels).1 The authors suggest that, because human CRP forms a doughnut-shaped pentameric structure, its binding to leptin may interfere with leptin’s passing through the blood-brain barrier to reach the medial hypothalamus, one of the features of leptin resistance.

For obese individuals, then, reduction of CRP is an important target. This is also very important for those at risk of heart attack. A recent paper2 suggests that the damage due to a heart attack can be reduced by quickly suppressing CRP levels with a CRP inhibitor. As a commentary on the paper notes,3 “CRP levels increase dramatically in patients with myocardial infarction, beginning 6 hours after the onset of ischemia and peaking at approximately 50 hours. CRP values after acute myocardial infarction predict outcome, including death and heart failure.”

VITAMINS It has been reported elsewhere4 that, “in a post hoc analysis of a randomized, double-blind, placebo-controlled study, multivitamin use was associated with lower C-reactive protein levels.” The multivitamin used was an ordinary, commercially available, 24-ingredient vitamin and mineral formulation. “After the intervention, the prevalence of a C-reactive protein level >3.0 mg/L decreased to 14% in the multivitamin group but increased to 32% in the placebo group (P<0.05 for difference at 6 months).” Niacin also reduces C-reactive protein levels.9

FIBER Another study5 reported that, in an examination of the association between dietary fiber and serum CRP using data from the National Health and Nutrition Examination Survey 1999–2000, it was found that “fiber intake is independently associated with serum CRP concentration and support the recommendations of a diet with a high fiber content.”

ARGININE A further study6 reported, after analyzing the Third National Health Nutrition and Examination Survey 1988–1994, that “the likelihood of having a high level of CRP (>3.0 mg/L), from the lowest to the highest level of arginine intake, were 34.8%, 31.0%, 27.7%, and 18.4%, respectively. In the adjusted regression, subjects in the highest level (90th percentile) of arginine intake were 30% less likely to have a CRP above 3.0 mg/L than were subjects with a median arginine intake (odds ratio = 0.70, 95% confidence interval = 0.56 to 0.88).”

HORMONE REPLACEMENT It has been reported that female hormone replacement with Premarin® conjugated horse estrogens increases levels of CRP.7 It is not clear, however, whether other types of hormone replacement (such as bioidentical human estrogen replacement) would have the same effect. Moreover, it appears that beginning hormone replacement shortly after menopause results in cardioprotective effects, while hormone replacement begun many years after menopause may not be protective or may actually be detrimental.

OTHER Life Extension magazine (March 2001) suggests that C-reactive protein may be suppressed by taking aspirin, vitamin E, DHEA, nettle leaf, and fish oils. Sleep loss has also been reported to increase CRP levels.8 Statins, weight loss, and exercise reduce CRP levels.9


  1. Chen et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nature Med 12(4):425-32 (2006).
  2. Pepys et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 440:1217-21 (2006).
  3. Kitsis and Jialal. Limiting myocardial damage during acute myocardial infarction by inhibiting C-reactive protein. New Engl J Med 355:513-5 (2006).
  4. Church et al. Reduction of C-reactive protein levels through use of a multivitamin. Am J Med 115:702-7 (2003).
  5. Ajani at al. Dietary fiber and C-reactive protein: findings from National Health and Nutrition Examination Survey data. J Nutr 134:1181-5 (2004).
  6. Wells et al. Association between dietary arginine and C-reactive protein. Nutrition 21:125-30 (2005).
  7. van Baal et al. Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women. Thromb Haemost 81:925-8 (1999).
  8. Meier-Ewert et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol 43(4):678-83 (2004).
  9. Backes et al. Role of C-reactive protein in cardiovascular disease. Ann Pharmacother 38(1):110-8 (2004).

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