The Medical Student Notebook

| November 2, 2014

This column is written by medical students and is dedicated to reviewing the science behind obesity and bariatric surgery.

Lesson #1 explores topics in gastrointestinal physiology and discusses the implications of gastric bypass surgery for each subject.

Column Editor: Daniel B. Jones, MD, MS, FACS
Professor of Surgery, Harvard Medical School
Vice Chair, Beth Israel Deaconess Medical Center
Boston, Massachusetts

Featured Student: Kyle D. Checchi, MSc
Medical Student, Harvard Medical School, Boston, Massachusetts

This month: Lesson #1: Bariatric Physiology
Parts 4 and 5: Leptin, Ghrelin, and Bariatric Surgery
by Kyle D. Checchi, MSc

FUNDING: No funding was provided for this article.
FINANCIAL DISCLOSURES: The author reports no conflicts of interest relevant to the content of this article.

Bariatric Times. 2014;11(11):8–9.

Introduction
Lesson #1 of The Medical Student Notebook is a five-part series focused on gastrointestinal physiology. Part 1, published in Bariatric Times March 2014, discussed bariatric surgery and B12. In Lesson #1, Part 2, published in Bariatric Times June 2014, we examined bariatric surgery and iron. In Lesson #1, Part 3, we discussed insulin physiology and type 2 diabetes mellitus (T2DM) in bariatric surgery. In Parts 4 and 5, we will explore the connections between obesity, bariatric surgery, and the physiology of two important hormones—leptin and ghrelin. Leptin and ghrelin are hormones that affect satiety, hunger, energy balance, and metabolism through peripheral and central nervous system effects. Understanding the role of these hormones and their relation to obesity and the effects of bariatric surgery is a critical area of research and could provide important insights to the practice of bariatric surgery and the management of obesity.

Part 4: Leptin and Bariatric Surgery
Leptin is the “satiety” hormone that is made primarily in fatty tissue, but also in the placenta, skeletal muscle, and the stomach.[1] Its activity is primarily as an indicator of fatty tissue for the brain, where it works as an anorexigenic signal to the hypothalamus and other neural pathways in the central control of feeding and energy balance.[2] Increases in blood leptin levels lead to satiety and increased energy usage. It is also postulated that there may be a component of leptin resistance in individuals with obesity.[3] In this mechanism, desensitization for the leptin signal through decreased transport of leptin across the blood-brain barrier, abnormalities in the extent of leptin receptor activation, or impaired signal transduction would result in inappropriately low levels of satiety and energy expenditure.[3]

Leptin may also be important in the mechanism of bariatric surgery. It has been observed that leptin levels drop significantly after gastric bypass surgery.[4] It has also been observed that the decrease in leptin levels occurs before substantial weight loss occurs following bypass surgeries;5 whereas decreasing leptin after bariatric surgery might be expected to decrease satiety and energy expenditure. This observation suggests that bariatric surgery may work by decreasing or reversing leptin resistance. The conclusion is that it is possible that impairment of leptin signaling to the hypothalamus may exert a central role in the development of obesity which may be reversible through bariatric operations.

Part 5: Ghrelin and Bariatric Surgery
Ghrelin as described thoroughly in Obesity Surgery: Principles and Practice by Pitombo et al,[6] is the “hunger” hormone made primarily in the stomach and duodenum.[6] It is the only known circulating orexigen and its activity is on the hypothalamus, caudal brainstem, and midbrain reward centers where it stimulates appetite and the initiation of meals.[6] Additionally, it has anabolic effects on food intake, energy expenditure, and fuel utilization.6 As evidence of its critical role in obesity, it has been shown that chronic ghrelin administration increases body weight and blockade of ghrelin signaling decreases body weight.[7,8]

Ghrelin likely also plays a role in bariatric surgery mediated weight loss, especially in gastric bypass surgery. In rat models, two studies showed significant decreases in ghrelin levels despite weight loss.[6] In human models, 15 of 17 studies demonstrated decreased ghrelin levels despite weight loss.[6] One possible explanation is “override inhibition,” where the stomach and duodenum are prevented from initiating ghrelin release because these segments are no longer in contact with ingested material after the bypass procedure.[9] It is also possible that the signal is disrupted through denervation of autonomic input to the stomach and duodenum that happens during the gastric bypass proceedure.10

Therefore, while the physiology and interaction of gastric bypass and ghrelin are not completely understood, it is possible that ghrelin may play a direct role in the neuro-hormonal component of gastric bypass surgery.

As with the conclusions in Parts 1 through 3, this discussion on leptin and ghrelin shows that physiology plays an important role in understanding obesity and its treatment. However, unlike in previous parts, the science surrounding leptin and ghrelin and bariatric surgery has yet to be settled, making these hormones promising subjects of future research. Increased understanding of the hormonal mechanisms of bariatric surgery could suggest and enable future medical therapies for obesity or lead to modifications of surgical technique. Until then, bariatric surgery remains the only proven consistent treatment for refractory morbidly obesity and provides another example of surgery method of modifying metabolic physiology and correcting pathophysiology.

References
1.    Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem. 2004;50(9):1511–1525.
2.    Longo D, Fauci, A, Kasper, D, et al. Harrison’s Principles of Internal Medicine, 18th Edition McGraw Hill Professional, 2011.
3.    Zabeau L, Lavens D, Peelman F, et al. The ins and outs of leptin receptor activation. FEBS Letters. 2003; 546(1):45–50.
4.    Holdstock C, Engström BE, Ohrvall M, et al. Ghrelin and adipose tissue regulatory peptides: effect of gastric bypass surgery in obese humans. J Clin Endocrinol Metab. 2003;88(7):3177–3183.
5.    Molina A, Vendrell J, Gutiérrez C, et al. Insulin resistance, leptin and TNF-alpha system in morbidly obese women after gastric bypass. Obes Surg. 2003;13(4):615–621.
6.    Pitombo C, Jones K, Higa K, Pareja J. Obesity Surgery: Principles and Practice. McGraw-Hill Medical, 2008.
7.    Wortley KE, del Rincon JP, Murray JD, et al. Absence of ghrelin protects against early-onset obesity. J Clin Invest. 2005;115(12):3573–3578.
8.    Zigman JM, Nakano Y, Coppari R, et al. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest. 2005;115(12):3564–3572.
9.    Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. NEJM. 2002:346(21):1623-1630.
10.    Williams DL, Grill HJ, Cummings DE, Kaplan JM. Vagotomy dissociates short-and long-term controls of circulating ghrelin. Endocrinology. 2003;144(12):5184–5187.

Category: Past Articles, The Medical Student Notebook

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