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Sex affects metabolism and glucose homeostasis through multiple mechanisms


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4 minutes

Sex is an obvious metabolic differentiator. Fat deposition in human obesity is sexually dimorphic. Males accumulate more visceral fat in an apple shape, while women accumulate more subcutaneous fat in a pear shape.

Matthew S. Rodenheffer, PhD
Matthew S. Rodeheffer, PhD

“There are two cellular mechanisms of white adipose tissue growth, hypertrophy and hyperplasia,” said Matthew S. Rodeheffer, PhD, Associate Professor of Comparative Medicine, Yale School of Medicine. “Hypertrophy, an increase in cell size, is a dynamic process as adipocytes gain and lose lipid content. Hyperplasia, the proliferation and differentiation of new adipocytes, is irreversible. Newly differentiated adipocytes remain for the rest of your life.”

Dr. Rodeheffer opened a symposium focusing on How Sex Shapes Metabolism and Glucose Homeostasis.

Adipocyte precursors are transiently activated by a high-fat diet, and sex influences the patterning of adipocyte hyperplasia. The estrus surge in female mice enhances obesogenic proliferation. Estrogen treatment alone can drive proliferation in both female and male mice, Dr. Rodeheffer explained.

Estrogen signals via estrogen receptor alpha (ERα) to promote obesity and obesogenic hyperplasia in females. Following menopause, women tend to switch to male-type accumulation of visceral fat, which parallels an increase in metabolic risk to male-like levels.

Yong Xu, MD, PhD
Yong Xu, MD, PhD

Three factors affect sex-based differences in metabolism. The most obvious factor is gonadal hormones, testosterone and estradiol, and their receptor signaling, said Yong Xu, MD, PhD, Professor of Pediatrics and Nutrition and of Molecular and Cellular Biology, Baylor College of Medicine.

The most fundamental category is sex-linked chromosomes. Multiple X-linked genes have been implicated in metabolic function and dysfunction.

“The most ignored category is autosomal genes because people do not always think to use both male and female animals to study these genes,” Dr. Xu said. “There is a short and increasing list of autosomal genes important in metabolism.”

Estradiol acts on ERα in the brain to regulate metabolism, he explained. Different ERα populations in different segments of the brain can affect food intake, energy expenditure, basal metabolism, thermogenesis, physical activity, and other metabolic functions.

Membrane-bound ERα, but not the nuclear receptor, plays a role in weight gain. About 300 different proteins interact with membrane-bound ERα, but chloride intracellular channel 1 (CLIC1), mediates rapid estradiol activity to excite neurons. Loss of CLIC1 in membrane-bound ERα neurons blunts estrogenic activity on weight on a high-fat diet.

Franck Mauvais-Jarvis, MD, PhD
Franck Mauvais-Jarvis, MD, PhD

Franck Mauvais-Jarvis, MD, PhD, Professor and Director of the Tulane Center of Excellence in Sex-Based Biology and Medicine, Tulane University School of Medicine, explained that sex is a genetic modifier of both biology and disease, including diabetes. The Women’s Health Initiative hormone trial demonstrated a protective effect for sex hormones until menopause, an effect that can be extended with menopausal hormone therapy.

“Males and females are two different biological systems,” Dr. Mauvais-Jarvis said.

ERα plays a role in glucose homeostasis in both male and female mice, he continued, but not the same role.

In female mice, lack of nuclear ERα produces insulin resistance associated with decreased hepatic interleukin 6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) activation. In male mice, lack of nuclear ERα downregulates glucose-stimulated insulin secretion by decreasing glucose sensing in the brain.  

And just as menopausal hormone therapy can protect women from developing type 2 diabetes, testosterone therapy in hypogonadal men can protect against type 2 diabetes. But estradiol and testosterone act through different mechanisms.

In female mice, estradiol regulates glucose homeostasis via the brain to affect skeletal muscle and hepatic activity. In male mice, testosterone acts via the brain to affect insulin secretion and adipose tissue to maintain glucose homeostasis.  

Joni Nikkanen, PhD
Joni Nikkanen, PhD

Joni Nikkanen, PhD, Postdoctoral Fellow, University of California, Berkeley, discussed the molecular origins of sex-biased diseases.

Disease has three primary causes: genetic dysfunction, infection, and environmental insults. These factors can act singly or in combination and are subject to evolutionary adaptations. Variants in a specific hemoglobin gene are protective against malaria, an infectious disease, but predispose for sickle cell anemia.

“Similar evolutionary trade-offs can underlie sex-based differences in metabolic disease patterns,” Dr.  Nikkanen said.

Mortality from E. coli infection in mice on a high-fat diet is sex neutral at room temperature, he noted, but in a thermoneutral environment, females are more likely to die than males.

Infection-induced hyperlipidemia, specifically hypertriglyceridemia, is the culprit, he explained. Male mice are protected by hepatic B-cell lymphoma 6 (BCL6), a critical modulator of hepatic lipid metabolism. Deleting hepatic BCL6 feminizes the female liver and male mice die at the same rate as female mice.

But there is a sexual trade-off: Male mice develop more severe fatty liver than females. Deleting BCL6 in males prevents hepatic lipid accumulation.  

Gonadectomy of male mice decreases BCL6 expression, but growth hormone, not testosterone, regulates BCL6 expression in primary hepatocytes, Dr. Nikkanen said. There is also a growth hormone receptor variant in humans, deletion of growth hormone receptor exon 3 (GHRd3), that feminizes the male liver.

GHRd3 protects against severe acute malnutrition, a protective factor in regions subject to severe famine. Sex-based expression of BCL6 is one reason more females survive famine than males, he added.