Menopause, Metabolism, and Visceral Fat Accumulation

Our bodies, anthropologically, function solely to reproduce in order to preserve our species. But reproduction requires adequate metabolic energy. Witness the increase in body fat as one enters puberty or the negative effect on fertility for patients with anorexia nervosa, for those engaging in strenuous exercise, or those subjected to famine and starvation. Yet, as our ability to reproduce ceases at the other end of the age spectrum, we experience a reduction in metabolism, redistribution of fat to our abdominal area and, thus, the cardiovascular and diabetic risks of metabolic syndrome. The key to these interactions resides in our hypothalamus where reproduction and metabolism are controlled.

 

Reproduction is initiated by three small groups of neurons in our hypothalamus called the KNDy neurons (kisspeptin, neurokinin B, and dynorphin) pronounced “candy.” In the adolescent child, as puberty approaches, suppressor genes that have kept these neurons quiet since birth lose their inhibitory effect. These KNDy neurons, with direct connections to our gonadotrophin-releasing hormone (GnRH) neurons, stimulate the release of gonadotrophin-releasing hormone (GnRH). GnRH, in turn, activates the pituitary to produce pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH), both of which stimulate the ovaries to begin to produce cyclic estrogen and progesterone, and the reproductive cycle begins.

 

These KNDy neurons, however, also play an important role in regulating metabolism by responding to feedback from peripheral hormones that are responsible for appetite and nutritional absorption. While more complex than stated here, in brief, leptin released from our white fat and insulin from our pancreas decrease our appetite and tell us to eat less. In contrast, ghrelin, from our gut, increases our appetite, usually causing us to eat more. Evidence that our metabolism and reproductive function interact is demonstrated by the fact that caloric restriction leading to ghrelin secretion reduces pulsatile GnRH release from the gonadotrophin-releasing neurons, thereby impairing ovulation.

 

Although metabolism and reproduction must work collaboratively, reproductive processes do not respond directly to metabolic cues. For example, GnRH neurons have no leptin or ghrelin receptors, and KNDy neurons have no ghrelin receptors. The higher order control of metabolism to support reproduction is believed to reside at the arcuate nucleus in the hypothalamus, which has access to circulating molecules outside the blood-brain barrier. It also has receptors for leptin, insulin, and ghrelin, and contains regulators of the KNDy and GnRH neurons.

 

Connecting the dots, however, has left us with one question: “Why does visceral fat form in the months or years leading into menopause?”

 

The initiating factor may be fluctuation and then loss of ovarian estradiol with its anti-inflammatory properties in the menopause transition, thus altering the immune characteristics of our intestinal bacteria and their control over nutritional absorption. Falling estradiol levels also produce alterations in KNDy neurons (now believed to be the origin of hot flashes) and could facilitate changes in how we metabolize our food. Evidence supporting this theory is found in breast cancer patients treated with aromatase inhibitors who have lowered estrogen levels and both an increasing incidence of hot flashes and increasing abdominal obesity. A contrasting theory, supported by animal and clinical studies, indicates an association between higher androgen levels and visceral fat accumulation. Perhaps both low estrogen and relatively elevated androgen levels contribute to the development of metabolic syndrome phenotype in genetically predisposed perimenopausal women. Other hormones, like thyroid hormone and cortisol, obviously have some role in this process as well.

 

Visceral fat cells, although only a small component of our overall body fat, accumulate non-esterified free fatty acids faster than subcutaneous fat cells. These visceral fat cells deliver free fatty acids (FFA) via the portal vein directly to our liver, thus contributing a higher proportion of overall hepatic FFA in individuals with greater visceral fat. The results are an increase in very low density lipoproteins (VLDL) and insulin resistance, hallmarks of type 2 diabetes and increased cardiovascular risk.

 

The biologies of reproduction and of metabolism, once thought of as silos, now seem more integrated. This observation raises new possibilities for novel treatments to prevent metabolic syndrome.

 

By James Woods, M.D. and Elizabeth Warner, M.D.
Dr. Woods treats patients for menopause at the Hess/Woods Gynecology Practice.

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