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The intricate interplay among body weight, stress, and the immune response to friend or foe
Lawrence Steinman,1 Paul Conlon,2 Rich Maki,2 and Alan Foster2
1Interdepartmental Program in Immunology and Department of Neurological Sciences, Stanford University, Stanford, California, USA2 Neurocrine Biosciences, San Diego, California, USA
Address correspondence to: Lawrence Steinman, Interdepartmental Program in Immunology and the Department of Neurological Sciences, Stanford University, B002 Beckman Center for Molecular Medicine, Stanford, California 94205, USA. Phone: (650) 725-6401; Fax: (650) 725-0627; E-mail: steinman@stanford.edu.
Find articles by Steinman, L. in: JCI | PubMed | Google Scholar
1Interdepartmental Program in Immunology and Department of Neurological Sciences, Stanford University, Stanford, California, USA2 Neurocrine Biosciences, San Diego, California, USA
Address correspondence to: Lawrence Steinman, Interdepartmental Program in Immunology and the Department of Neurological Sciences, Stanford University, B002 Beckman Center for Molecular Medicine, Stanford, California 94205, USA. Phone: (650) 725-6401; Fax: (650) 725-0627; E-mail: steinman@stanford.edu.
Find articles by Conlon, P. in: JCI | PubMed | Google Scholar
1Interdepartmental Program in Immunology and Department of Neurological Sciences, Stanford University, Stanford, California, USA2 Neurocrine Biosciences, San Diego, California, USA
Address correspondence to: Lawrence Steinman, Interdepartmental Program in Immunology and the Department of Neurological Sciences, Stanford University, B002 Beckman Center for Molecular Medicine, Stanford, California 94205, USA. Phone: (650) 725-6401; Fax: (650) 725-0627; E-mail: steinman@stanford.edu.
Find articles by Maki, R. in: JCI | PubMed | Google Scholar
1Interdepartmental Program in Immunology and Department of Neurological Sciences, Stanford University, Stanford, California, USA2 Neurocrine Biosciences, San Diego, California, USA
Address correspondence to: Lawrence Steinman, Interdepartmental Program in Immunology and the Department of Neurological Sciences, Stanford University, B002 Beckman Center for Molecular Medicine, Stanford, California 94205, USA. Phone: (650) 725-6401; Fax: (650) 725-0627; E-mail: steinman@stanford.edu.
Find articles by Foster, A. in: JCI | PubMed | Google Scholar
Published January 15, 2003 - More info
J Clin Invest. 2003;111(2):183–185. https://doi.org/10.1172/JCI17622.
© 2003 The American Society for Clinical Investigation
We all know that when we suffer from fever we feel sleepy and do not feel like eating. Our mothers and grandmothers provided sound wisdom during our bouts of illness with fever. They recommended rest and tried to make us eat, advocating folk remedies like chicken soup or various teas. The physiologic roles of mediators of fever such as IL-1, TNF-α, IL-6, and prostaglandins account for some of the physiological changes in the sleep/wake cycle and in appetite (1, 2). Prostaglandins are involved in the induction of sleep, while TNF-α triggers loss of appetite and pyrexia. However, we are now learning that the interconnections between molecules that modulate brain function and those that mediate the immune response are more intertwined than we had previously imagined.
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Neuropeptides involved in body weight are found at sites of autoimmunity
There are indications that other neuroendocrine mediators such as the melanocortins (12, 13) and CRF (2, 12, 13) also have prominent roles in diseases like MS and rheumatoid arthritis, which are thought to be autoimmune in nature. Leptin is thought to produce its profound effects on appetite and body weight by altering the balance between the anorectic neuropeptides α-melano-cyte–stimulating hormone (α-MSH) and CRF and the orexigenic neuropeptides agouti-related peptide and neuropeptide Y. Shifts in the balance between these types of neuropetides also contribute to the cytokine-mediated loss of appetite and body weight, as well as malaise induced by lipopolysaccharide (14). One important aspect of this regulation is at the level of the pro-opiomelanocortin–expressing neurons in the arcuate nucleus of the hypothalamus, which are activated by leptin to release α-MSH (15). Apparently, this in-terplay of neuropeptides with re-gards to hypothalamic function may be reproduced at sites of autoimmune pathology (Figure 1). Large-scale analysis of gene transcripts in MS lesions revealed that leptin, melanocortin 4 receptor, and ACTH-receptor are elevated at the site of inflammation in the brain (12, 13). All three of these neuropeptides — leptin, melanocortin 4, and ACTH — have pleiotropic roles in neuroendocrine and immune physiology.
Figure 1Body fat and the autoimmune response. Decreases in body fat or starvation increase CRF levels and decrease leptin levels. Increased CRF downregulates Th1 immunity (5) as does decreased leptin (4). Other molecules of the α-MSH family stimulate Th1 T cells via their MC-4 receptor. CRFR, CRF receptor; LepR, leptin receptor.
The microsomal enzyme, stearoyl CoA desaturase–1 (SCD-1), is required for the biosynthesis of the monounsaturated fats, palmitoleate and oleate from saturated fatty acids (16). SCD-1 RNA levels are highly elevated in untreated ob/ob mouse liver, and indeed SCD-1 probably plays a decisive role in leptin’s metabolic effects. Interestingly, SCD-1 was downregulated in the MS brain as well (12), and both RNA levels and the activity of this enzyme are repressed by leptin (16). Ob/ob mice with mutations in SCD-1 are significantly less obese than ob/ob controls (16). The role of leptin in autoimmune brain disease and in the immune system in general may be mediated by downregulation of this enzyme involved in the biosynthesis of monosaturated fats. Once again we witness the remarkable choreography of molecules related to body weight and energy metabolism and the parallel roles of these same molecules in the finely tuned immune response.
Earlier work showed that CRF, the key regulator of the stress response in the hypothalamic-pituitary-adre-nal axis, or urocortin, a naturally occurring paralogue of CRF, acting directly on T cells in adrenalectomized mice, ameliorated experimental autoimmune encephalomye-litis. These effects were blocked by antagonists of CRF (5). Thus CRF, like leptin, is produced by the brain and may act directly on the immune system. The expression of CRF itself can be regulated by cytokines, adding yet another layer of complexity and a further target for intervention. Another neuropeptide, ACTH, a key mediator of the stress response produced in the pituitary gland, has been used for over 40 years to treat MS. ACTH receptor is expressed in the MS lesion itself (12).
These results imply that in autoimmunity, stress may be beneficial, and that short-term starvation may help reverse disease. In fighting microbial infections, perhaps stress is detrimental and eating is recommended, but in the case of autoimmunity, the opposite holds true: stress is actually good for you, and starvation is helpful. Grandmother’s advice may have to be refined depending on whether the immune system is attacking friend or foe.
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