α-MSH, regulator of appetite and weight and our bone matrix. (& we need Zinc too!)

Production of α-MSH is promoted by leptin and α-MSH can inhibit leptin production, suggesting a feedback loop during normal function. Obesity often has elevated leptin & lack of receptors.

α-Melanocyte-stimulating hormone (α-MSH) is involved in more than melanin production. It also has regulatory effects on appetite and body weight and leptin levels would affect production of α-MSH. It affects bone mass negatively in animal-based research and was found to increase osteoclasts (Cornish, et al, 2003) which breakdown bone matrix. Quantities of a hormone used in the study might have been more than would be promoted by smelling spring flowers. *This is a continuation or tangent following the last post: VEGF, galactin-3, chimeric spike, and milk sugar. (substack.com).

Addition - the nutshell point seems to be that sunshine helps us to not be overweight (sun>α-MSH), but too much sun and α-MSH may add to osteoporosis risk. And leptin is complex and deserves its own 16-page equivalent post before I can provide a nutshell. Highlights - Leptin is cytokine like and structurally similar to interleukins IL-2 and IL-6. Deficiency has negative impacts on immune function and thymus T-cell growth. “Leptin stimulates thymic functions and the proliferation of CD+4 -T cells, and has a stimulating effect on Th1 cells and an inhibiting effect on Th2 cells.[41]” (Baltaci and Mogulkoc, 2012) While excess is seen in obesity along with too few leptin receptors, leptin’s main function in appetite is to promote satiety.

Lack of zinc led to less leptin, but the reason why is not known. (Baltaci and Mogulkoc, 2012) It likely involves the need for zinc to make zinc finger proteins which are involved in gene transcription and adipocyte growth for white and brown adipose tissue. (Wei, et al, 2013)

Back to the post:

“α-Melanocyte-stimulating hormone (α-MSH), a 13-amino acid peptide produced in the brain and pituitary gland, is a regulator of appetite and body weight, and its production is regulated by leptin, a factor that affects bone mass when administered centrally. α-MSH acts via melanocortin receptors.” (Cornish, et al, 2003)

Leptin promotes production of α-MSH in the pituitary gland, but α-MSH is also involved in regulation of leptin production, inhibiting it - “suggesting a feedback loop”.

There is increasing evidence of a peripheral action of melanocortins in the regulation of leptin production by adipocytes. Here we investigate the interaction of alpha-melanocyte stimulating hormone (alpha-MSH) and agouti-related protein (AgRP) in the regulation of leptin secretion from cultured rat adipocytes and examine the changes in circulating alpha-MSH and AgRP in lean and obese rodents after hormonal and energetic challenge. Leptin secretion (measured by ELISA) and gene expression (by real-time quantitative PCR) of differentiated rat adipocytes cultured in vitro were inhibited by the administration of alpha-MSH (EC50=0.24 nM), and this effect was antagonised by antagonists of the melanocortin receptors MC4R and MC3R (AgRP and SHU9119). The presence of MC4R in rat adipocytes (RT-PCR and restriction digest) supports the involvement of this receptor subtype in this interaction. Leptin administered to ob/ob mice in turn increases the release of alpha-MSH into the circulation, suggesting a possible feedback loop between the site of alpha-MSH release and the release of leptin from the adipose tissue. However, the physiological significance of this putative feedback probably depends upon the underlying state of energy balance, since in the fasting state low plasma alpha-MSH is paralleled by low plasma leptin. (Hoggard, et al, 2004)

In normal appetite and health, an increase in leptin would signal, “Stop eating, full now”.

Photo by Peter Dawn on Unsplash

Leptin excess leading to leptin resistance is seen in obesity and overweight conditions. (Scarpace and Zhang, 2007) Leptin is supposed to tell us we are satisfied and to stop eating but it doesn’t seem to work normally once excess weight is gained. Fewer receptors that are not responsive occur in response to the elevated leptin levels.

Maybe there is a gene transcription problem, why aren’t the receptors being made? Some sort of signaling to do so, or dysfunction?

Abstract - nice overview, there may be more recent findings:

Leptin is an adipocyte-derived, satiety-regulating hormone that acts within the hypothalamus and other brain sites. Obese humans and animals are largely resistant to central actions of leptin. Rising leptin levels associated with progressing obesity are generally regarded as simply a consequence rather than a causative factor in the leptin resistance and obesity. Several lines of evidence suggest otherwise. Chronic overexpression of central leptin induces a leptin resistance that mimics many of the characteristics associated with diet-induced or adult-onset obesity including reduced leptin receptors, diminished signaling, and impaired responsiveness to exogenous leptin. Moreover, these animals have increased susceptibility to diet-induced obesity. New data with a leptin antagonist demonstrate that blockade of leptin receptors also exaggerates diet-induced obesity. These findings suggest an important role for elevated leptin in the development of leptin resistance and obesity, especially in today's society with an overabundance of readily available high caloric food. Once leptin resistance takes hold, each subsequent exposure to high-density food faces diminished counter-regulatory responses, leading to exacerbated weight gain. (Scarpace and Zhang, 2007)

Covid19 was a much more severe risk for patients who were more overweight, obese, or had Metabolic Syndrome. They were already inflamed and may already have had too much leptin with too few leptin receptors - and may have been zinc deficient.

Interesting IL-6 factoid (IL-6 can be elevated in Covid19, or cytokine storm/sepsis):

“Zinc deficiency also inhibited IL-6 secretion of the fatty tissue in these mice.[33] This is an interesting result as leptin and leptin receptors are structurally similar to IL-6.[33] In conclusion, it was demonstrated that metabolic defects that arise in mice with hyperglycemia induced by STZ could be restored by supplementation of zinc in physiological doses.” (Baltaci and Mogulkoc, 2012)

Zinc and leptin have been associated with obesity, but the reason is unclear in a review about the role of leptin and zinc in regulation of food intake and immunity. (Baltaci and Mogulkoc, 2012) It included an animal-based study on sucrose-induced obesity, the animals were low in zinc and providing zinc helped “ameliorate” the obesity, however, or because, leptin levels increased even more with the zinc supplementation. (Chen and Lin, 2000) However zinc deficiency led to less leptin production in fatty tissue in another study:

“A decrease was found in the ob mRNA content of the fatty tissue in rats fed on a zinc-deficient diet with a concomitant and significant decrease in leptin secretion from the fatty tissue.[34] More interestingly, a significant decrease was observed in the leptin secretion per gram of fatty tissue in zinc-deficient rats, when compared to their controls.[34]” (Baltaci and Mogulkoc, 2012)

Spoiler alert: They missed the effect of zinc transcribed bitter taste receptors in the gut, not just on the tongue, and their role in satiety and normal insulin levels. That is partially why severe zinc deficiency can cause anorexia, but milder zinc deficiency might lead to obesity - no longer sensing bitter tastes in the gut, which sends satiety signals to stop eating, there was enough bitter and other tastes in the meal, and body says done now, thanks!

Continuing though - really helpful insights into leptin’s role in immune function:

“Due to the similarity of leptin and leptin receptors to cytokines, leptin may also be classified as a cytokine.[38] It was argued that leptin might have a fundamental part in the production and maintenance of the immune response. Leptin structurally resembles IL-2 and IL-6 and is a critical T-cell growth factor.[39] Therefore, leptin deficiency increases predisposition to infections and this increase is associated with impairments in the production of cytokines.[40] Presence of leptin receptors in CD+4 and CD+8 lymphocytes is also evidence of the relation between leptin and immune functions.[41] Leptin stimulates thymic functions and the proliferation of CD+4 -T cells, and has a stimulating effect on Th1 cells and an inhibiting effect on Th2 cells.[41]” (Baltaci and Mogulkoc, 2012)

Adequate zinc is also needed to promote thymus function, and increased amounts are needed in aging. The US nutrient guidelines do not reflect that increased need for extra zinc for Senior Citizens.

It does sound like zinc and leptin - and bitter tasting phytonutrients are all team players for the function of a normal appetite and weight. Pomegranate has anti-osteoporosis benefits (animal-based study), (Spilmont, et al, 2015), and helps weight control and glycemic response. (González-Ortiz et al, 2011, Hassanpour fard, et al, 2015)

See this recent post for more about bitter tasting phytonutrients and their role in satiety:

Pomegranate for mitochondrial support (and zinc for a healthy weight too!)

In my own long years of yo-yo dieting and weight loss efforts - when it worked it was effortless for me, while “trying” various methods and exercising more, etc, may have chiseled off some weight but in no way was easy or permanent. I needed high dose iodine, topical magnesium, zinc and B6 in higher doses for pyroluria (untested but it works so I am happy, but forgetful and symptoms can return). Eventually I added thiamine and other Bs to my daily routine and used the methyl forms. Other changes were made but those were significant factors.

Disclaimer: This information is provided for educational purposes within the guidelines of Fair Use. It is not intended to provide individual guidance. Please seek a health care provider for individualized health care guidance.

Reference List

(Baltaci and Mogulkoc, 2012) Baltaci AK, Mogulkoc R. Leptin and zinc relation: In regulation of food intake and immunity. Indian J Endocrinol Metab. 2012 Dec;16(Suppl 3):S611-6. doi: 10.4103/2230-8210.105579. PMID: 23565497; PMCID: PMC3602991. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602991/

(Chen and Lin, 2000) Chen MD, Lin PY. Zinc-induced hyperleptinemia relates to the amelioration of sucrose-induced obesity with zinc repletion. Obes Res. 2000 Oct;8(7):525-9. doi: 10.1038/oby.2000.65. PMID: 11068958. https://pubmed.ncbi.nlm.nih.gov/11068958/

(Cornish, et al, 2003) Cornish J, Callon KE, Mountjoy KG, et al, α-Melanocyte-stimulating hormone is a novel regulator of bone, American Journal of Physiology-Endocrinology and Metabolism 2003 284:6, E1181-E1190 https://journals.physiology.org/doi/abs/10.1152/ajpendo.00412.2002

(Hoggard, et al, 2004) Hoggard N, Hunter L, Duncan JS, Rayner DV. Regulation of adipose tissue leptin secretion by alpha-melanocyte-stimulating hormone and agouti-related protein: further evidence of an interaction between leptin and the melanocortin signalling system. J Mol Endocrinol. 2004 Feb;32(1):145-53. doi: 10.1677/jme.0.0320145. PMID: 14765998. https://pubmed.ncbi.nlm.nih.gov/14765998/

(Scarpace and Zhang, 2007) Scarpace PJ, Zhang Y. Elevated leptin: consequence or cause of obesity? Front Biosci. 2007 May 1;12:3531-44. doi: 10.2741/2332. PMID: 17485319. https://pubmed.ncbi.nlm.nih.gov/17485319/

(Wei, et al, 2013) Wei S, Zhang L, Zhou X, Du M, Jiang Z, Hausman GJ, Bergen WG, Zan L, Dodson MV. Emerging roles of zinc finger proteins in regulating adipogenesis. Cell Mol Life Sci. 2013 Dec;70(23):4569-84. doi: 10.1007/s00018-013-1395-0. Epub 2013 Jun 13. PMID: 23760207; PMCID: PMC4100687. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100687/