Is Leptin Stimulated by Insulin Alone?

Question

What is the mechanism of insulin stimulation in the human body?

Is leptin release stimulated by circulating insulin directly? Which other factors are involved in the level of insulin release? My goal is to identify nutrients that aid/trigger leptin production and release without causing undue inflammation or body-fat storage.

Answer 1

I have to say that this seems like a really odd approach to figuring out your diet. The question of whether insulin increases satiety has been more specifically studied in the literature, as has the satiety generated by equicaloric portions of various kinds of foods, as have the actual effects of various specific diets in human feeding studies. If you do a bit of digging, I'm sure you can find studies relating high/low GI diets to medically important outcomes (weight loss, blood lipids, fasting insulin levels, etc.), as opposed to their effect on one proposed satiety/fat regulation hormone (leptin). Your approach also ignores leptin and insulin sensitivity, which might be as important as the levels themselves. As someone concerned with which foods to actually eat, empirical studies of actual diets seem like the best place to look.

Anyway, here are a few relevant citations to help answer your question:

This study found a increase in serum leptin levels in type I diabetic children who started insulin therapy: Flück CE, Kuhlmann BV, Mullis PE. "Insulin increases serum leptin concentrations in children and adolescents with newly diagnosed type I diabetes mellitus with and without ketoacidosis." Diabetologia. 1999 Sep;42(9):1067-70. http://www.ncbi.nlm.nih.gov/pubmed/10447517

A slightly smaller study asked the same question, and found no increase in leptin levels: McCormick KL, Mick GJ, Butterfield L, Ross H, Parton E, Totka J. "Leptin in children with newly diagnosed type 1 diabetes: effect of insulin therapy." Int J Exp Diabetes Res. 2001;2(2):121-7. http://www.ncbi.nlm.nih.gov/pubmed/12369715

An in vitro study of rat fat cells does indicate a direct increase in leptin secretion/production when given insulin: Barr VA, Malide D, Zarnowski MJ, Taylor SI, Cushman SW. "Insulin stimulates both leptin secretion and production by rat white adipose tissue." Endocrinology. 1997 Oct;138(10):4463-72. http://www.ncbi.nlm.nih.gov/pubmed/9322964 http://endo.endojournals.org/content/138/10/4463.full

...and in human fat cells: Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Englaro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner H. "Insulin and cortisol promote leptin production in cultured human fat cells." Diabetes. 1996 Oct;45(10):1435-8. http://www.ncbi.nlm.nih.gov/pubmed/8826983

Leptin levels are positively correlated with insulin levels and BMI (presumably as a proxy for fat mass?): Lambrinoudaki I, Christodoulakos G, Panoulis C, Botsis D, Rizos D, Augoulea A, Creatsas G. "Determinants of serum leptin levels in healthy postmenopausal women." J Endocrinol Invest. 2003 Dec;26(12):1225-30. http://www.ncbi.nlm.nih.gov/pubmed/15055477

Thierry Thomas, Bartolome Burguera, L.Joseph Melton III, Elizabeth J. Atkinson, W.M. O'Fallon, B.Lawrence Riggs, Sundeep Khosla, "Relationship of serum leptin levels with body composition and sex steroid and insulin levels in men and women" Metabolism Volume 49, Issue 10, October 2000, Pages 1278–1284 http://www.sciencedirect.com/science/article/pii/S002604950041783X

This study found a positive relationship between changes in insulin levels and leptin levels, though it sounds like only in women. (I don't have the full text to check, and the abstract was ambiguous): Widjaja A, Levy JC, Morris RJ, Frayn KN, Humphreys SM, Horn R, von zur Mühlen A, Turner RC, Brabant G. "Determinants of within-subject variation of fasting serum leptin concentrations in healthy subjects." Exp Clin Endocrinol Diabetes. 2000;108(3):208-13. http://www.ncbi.nlm.nih.gov/pubmed/10926318

So based on an incomplete and cursory literature search, it seems likely that injecting insulin increases leptin production, as do some other activities that tend to increase insulin. The evidence for causation in humans is not totally clear cut, though suggestive.

Answer 2

I agree - an odd approach to diet. Leptin does a lot and has several modes by which its expression is regulated. While the connections to insulin are well documented, I've brought to light here several other interesting characteristics of leptin.

LEP exerts its effects in the brain via the gene MC4R - see this.

HMGA1 strongly potentiates the capacity of the CEBPB (CCAAT/enhancer-binding protein beta) transcriptional factor to transactivate the LEP promoter (Esposito Fusco 2009 J Biol Chem 284:25998)

Subjects who watched a humorous video had changes in blood pressure and showed decreased levels of LEP as the level of GHRL increased, much like the acute effect of moderate physical exercise that is often associated with increased appetite.

After adjustment for gender and age SERPINF1 SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass and fasting leptin concentrations, as well as nominal associations with bioelectrical impedance-derived percentage of body fat and clamp-derived insulin sensitivity in humans, thus contributing to overall body adiposity, obesity-related insulin resistance and circulating leptin levels (Böhm Ordelheide 2012 PLoS One 7:e34035).

Leptin influences the development of eyes and ears in zebrafish and was shown by knockout to affect eye and ear development in mice (Londraville 2012 General Comparative Endocrinology J). There are many connections between blood lipids, lipid homeostasis and eye health; many genes important to both blood lipids and eye health are shared.

Lastly, the LEP gene shows altered H3K9/K14 acetylation in response to hyperglycemia (Pirola Balcerczyk 2011 Genome Res).

Answer 3

Leptin may not be as important as we think. A review in 2001 concludes:

Conversely, it is unlikely that leptin has evolved to prevent obesity when plenty of palatable foods are available because the elevated plasma leptin levels resulting from the increased adipose tissue mass do not prevent the development of obesity. In conclusion, in humans, the leptin signaling system appears to be mainly involved in maintenance of adequate energy stores for survival during periods of energy deficit. Its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal (mutations of the leptin gene or of the leptin receptor gene), which produces an internal perception of starvation and results in a chronic stimulation of excessive food intake.

However, in a newer review it looks as if leptin is involved in more processes than mere survival:

Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles.

Jéquier, Eric. "Leptin signaling, adiposity, and energy balance." Annals of the New York Academy of Sciences 967.1 (2002): 379-388. http://www.ncbi.nlm.nih.gov/pubmed/12079865

Gautron, Laurent, et al. "Sixteen years and counting: an update on leptin in energy balance." The Journal of clinical investigation 121.6 (2011): 2087. http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21633176/