Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring
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The function of the thyroid gland is to produce the thyroid hormones T3 and T4, which regulate gene transcription throughout the body (1). In medical practice, the thyroid becomes an issue when its size or shape becomes abnormal or when it produces too much or too little hormone. Thus, we typically think of the thyroid with reference to the clinical states of goiter, or hyper- or hypothyroidism. But what is the physiology of the thyroid when the gland and the entire hypothalamic-pituitary-thyroid axis are intact? As first year medical students ask each year, Why exactly do we have a thyroid, at all? The usual presentation of thyroid physiology does not stress dynamic changes in hormone levels. Unlike insulin or cortisol levels, which are widely understood to fluctuate in response to food ingestion and stress, respectively, thyroid hormones are typically thought to be maintained at a basal level of hormone that keeps the metabolic machinery humming at the proper rate. In our opinion, this static view of thyroid physiology is mistaken. Nutrition and thyroid hormones. In addition to changes in thyroid hormone that occur in development, from tadpoles to mammals, thyroid hormone levels are subject to major physiologic regulation during the transition from the fed to the starved state. In the well-studied rodent model, starvation rapidly suppresses T4 and T3 levels (2, 3). The benefit of this suppression is clear: Starvation represents a severe threat to survival, and, in rodents, the capacity to survive without nutrition is measured in days. Because thyroid hormones set the basal metabolic rate, a drop in thyroid hormone levels should reduce the obligatory use of energy stores. As long as hypothyroidism does not impair the ability to obtain food, this adaptation would be expected to enhance survival. Because animals in the wild are thought to commonly experience periods of starvation, the thyroid response to starvation should be viewed as a major aspect of the regulatory biology of the thyroid gland. The thyroid system is regulated at multiple levels, one or more of which might account for nutritional adaptation. First, thyrotropin-releasing hormone, a neuropeptide produced in the paraventricular nucleus (PVN) of the hypothalamus, controls the release of thyroid-stimulating hormone (TSH) from the pituitary. TSH acts on receptors on the thyroid to promote synthesis and release of the thyroid hormones T4 and T3. In addition, a family of deiodinases metabolize the less-active T4 to the more-active T3 or to the inactive reverse T3. In primary hypothyroidism, when T3 and T4 levels fall because of a defect within the thyroid, a 2-part compensatory system kicks in. In the PVN of the hypothalamus, TRH expression increases because of the lack of negative feedback by thyroid hormones (4). In the pituitary thyrotroph, TSH production increases due to both increased TRH production and decreased negative feedback by thyroid hormones on the genes encoding TSH subunits (5). The increased TSH serves to drive the failing thyroid and is the most sensitive test for the diagnosis of thyroid failure. Starvation appears to act, at least in part, by suppressing TRH expression in the PVN—although, interestingly, TRH continues to be expressed in the remainder of the central nervous system (CNS), which plays no role in regulating pituitary TSH production (2). TSH production falls, and simultaneously the pattern of glycosylation on newly synthesized TSH is altered so that the TSH that is produced is of reduced bioactivity (6). Thus, as a consequence of starvation, T4 and T3 levels fall, leading to central hypothyroidism. Leptin and the regulation of thyroid function by the brain. The mechanism by which the brain orchestrates this adaptation is now becoming increasingly clear. The dominant, and perhaps sufficient, signal to the brain that suppresses TRH expression in the PVN is a drop in the level of the hormone leptin. This 16-kD hormone is expressed predominantly in adipose cells, and its absence, as in the ob/ob mouse, produces severe obesity (7). Initially viewed primarily as a hormone designed to prevent obesity, a substantial body of work now suggests that leptin also signals the switch from the fed to the starved state (3, 8). A fall in leptin acts through the hypothalamus to increase appetite, decrease energy expenditure, and modify neuroendocrine function in a direction that favors survival. The consequences of falling leptin include suppression of reproduction, linear growth, and the thyroid axis, as well as activation of the stress axis (3). As with the mouse gene, mutation of the human leptin receptor gene can also cause obesity with central hypogonadism and hypothyroidism (9). As reviewed in ref. 10, much effort is now directed to understanding the precise neural circuits through which leptin brings about these effects on appetite and neuroendocrine function. With regard to thyroid activity, a cr
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Leptin insufficiency together with decreased insulin levels may act in conjunction to suppress melanocortin tone and limit weight loss via a reduction in T3 levels and energy expenditure.
“Thus, leptin insufficiency together with decreased insulin levels may act in conjunction to suppress melanocortin tone and limit weight loss via a reduction in T3 levels and energy expenditure.”
From Prospective study of gut hormone and metabolic changes after adjustable gastric banding and Roux-en-Y gastric bypass (2009) · cites this paper as [39]
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- Authors
- Flier, J. S., Harris, M., & Hollenberg, A. N.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Flier, Jeffrey S.
- Venue
- Journal of Clinical Investigation
- Published
- 2000-04-01
- Volume
- 105
- Issue
- 7
- Pages
- 859-861
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC377492
- OpenAlex
- W2105429765
- Cited by
- 230
- References
- 18
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 10 · 2023: 8 · 2022: 9 · 2021: 10 · 2020: 7 · 2019: 6 · 2018: 10 · 2017: 8 · 2016: 5 · 2015: 7 · 2014: 8 · 2013: 5 · 2012: 7
- FWCI
- 9.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- leptin, thyroid hormones, thyroid physiology, hypothalamic-pituitary-thyroid axis, starvation, nutritional adaptation, thyrotropin-releasing hormone, thyroid-stimulating hormone, deiodinases, reverse T3, T3/T4 ratio, basal metabolic rate, hypothalamic paraventricular nucleus, hypothyroidism, hyperthyroidism
- MeSH terms
- alpha-MSH, Animals, Brain, Proteins, Starvation, Thyroid Gland, Thyroid Hormones, Thyrotropin, Thyrotropin-Releasing Hormone, Receptors, Corticotropin, Leptin, Intercellular Signaling Peptides and Proteins, Receptors, Melanocortin, Agouti-Related Protein
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