Sex-Based Differences Regarding Obesity and Diabetes

Sex hormones, adiposity and metabolism differences between men and women have researchers examining how estrogen, androgens and adipose tissue affect obesity and Type 2 diabetes. Research has shown that premenopausal women have lower rates of diabetes than men and women who have gone through menopause. Cedars-Sinai Diabetes and Obesity Research Institute (DORI) scientists are focused on understanding the role of estrogen in protecting against diseases associated with obesity and metabolic syndrome.

In addition to being important in reproduction, estrogen receptor alpha (ERα) is key in energy regulation. Estrogen receptors are shown to influence metabolism, obesity, cardiovascular disease, fat distribution, polycystic ovary syndrome, breast cancer, prostate cancer, epigenetics and maternal fetal programming. Estrogens have been shown to regulate metabolism, perhaps by acting as a leptin mimetic in the central nervous system (CNS) and periphery in the regulation of energy homeostasis.

Deborah Clegg, PhD, is a researcher with DORI and a professor in the department of Biomedical Sciences. Her research uses rodent models to test whether androgens and estrogens are involved in the modulation of pathways that normally support metabolic function. Clegg's focus is to better understand the interactions between nutrients, estrogens and obesity in patients who develop breast cancer and Type 2 diabetes.

Sex hormones in women have been shown to be protective in regulating weight and browning of fat. Following gastric bypass surgery, fat in men doesn't brown the way it does in women. Recent research also suggests that women's fat cells may be healthier than men's, in that women's fat cells expand to absorb the fat from a meal and prevent it from circulating in the bloodstream, whereas in men, extra calories turn into lipid droplets that course through the body.

Current studies include:

  • Investigate hormonal regulation of fat deposition to determine and track adipose lineage during menopause, as well as tracking and following estrogen replacement
    • Examine mechanisms that control formation and remodeling of adipose tissue to determine whether and how remodeling of adipose tissue is altered by estrogen signaling.
    • Identify, engineer and study mice that express molecular reporters in adipose lineage.
    • Visualize adipose stem cells in vivo and follow their descendants as they divide, migrate and develop into mature adipocytes.
    • Access estrogen-dependent remodeling.
    • Delineate how estrogen remodels adipose tissue relative to adipose tissue deposition including intra-abdominal (visceral) adipose tissue, which increases with menopause, and subcutaneous adipose tissue (induced by estrogen).
    • Integrate surgical (ovariectomy), pharmacological (estrogen) and genetic (adipose-lineage-specific estrogen receptor knockouts) manipulations to model these morphogenic transformations and determine how they affect adipose lineage specification using our newly developed mice.
    • Define the mechanistic underpinnings of the estrogenic-remodeling effects on adipose stem cells, adipose niche cells and adipocytes, and elucidate how physiological and pharmacological stimuli regulate the stem population and the growth of adipose tissue.
    • Determine new aspects of adipose biology and metabolic control and how estrogen provides a protective effect, highlighting those that are relevant to new therapies for obesity and diabetes.
  • Estrogen reduces inflammation through ERα
    • Examine the anti-inflammatory properties that the estrogen receptor ERα exerts peripherally in adipocytes and centrally in proopiomelanocortin (POMC)-positive neurons.
    • Observe how peripheral tissues, such as adipose tissue, convey metabolic signals to the CNS, and how these signals are communicated back to the periphery, such as the liver.
    • Study the specific role of inflammatory signals in this process by focusing on pro- and anti-inflammatory actions of several proteins in adipose tissue and within the CNS, such as the hypothalamus and the vagal afferent neurons in the nodose ganglia.
    • Determine the role of estrogen in mediating anti-inflammatory properties through ERα both peripherally (in adipocytes) and centrally (in POMC -positive neurons).

Female adipose tissue is more insulin sensitive, less susceptible to inflammation and has higher expression of estrogen receptors than male adipose tissue, due in part to ERα. The translational research being done will ideally elucidate opportunities to reduce obesity as well as the risk for metabolic diseases including cardiovascular diseases, Type 2 diabetes and cancers.

Previous research