How does obesity cause ill-health?

Obesity is associated with several medical problems, particularly type 2 diabetes. But how excess body fat causes illness is not completely understood.

Increasing body mass index is linked to increased risk for a range of conditions, including high blood pressure, gallstones, cancer and, most clearly, type 2 (adult-onset) diabetes.

Obesity and diabetes

Type 2 diabetes arises when the body's cells become less sensitive to the action of insulin (insulin resistance) and beta cells in the pancreas release insufficient insulin. Blood glucose levels rise, which has a number of harmful effects: in the short term, fatigue and dizziness; in the longer term, a variety of complications including kidney damage, eye problems and nerve damage. There is a very clear link between diabetes and obesity – 80 per cent of people with type 2 diabetes are obese.

But why does being obese affect the insulin system? Working out the biochemical links has been surprisingly difficult – and is still not completely understood.

A currently popular theory is that defective lipid metabolism is to blame. Fat molecules leak out of adipose (fat-storing) cells and are taken up by muscle and liver cells. The fat molecules interfere with the signalling pathways within the cell that convey a message from the insulin receptor at the cell surface to the nucleus. This impairs the cell's ability to respond to insulin.

Obesity also triggers an inflammatory response in the body, which may also contribute to diabetes. For example, levels of a pro-inflammatory signalling molecule known as TNFα (tumour necrosis factor α) are raised, which is also known to interfere with intracellular signalling in insulin-responsive cells.

Adipose tissue used to be thought of as just a storage tissue. But it is clear that it is much more active than that, and is now thought to be a kind of endocrine gland, releasing hormones and other signaling molecules (adipocytokines). These may also be involved in disrupting responses to insulin.

Obesity and cancer

Being obese increases the risk of dying from a number of types of cancer. What are the mechanisms involved?

Again, an important factor appears to be the release of hormones or other signalling molecules by adipose cells. These can affect the growth and proliferation of cells, and promote uncontrolled growth of cells to create a cancer.

One example is breast cancer, the risk for which is increased in post-menopausal obese women. Potentially important factors include secretion of the female hormone oestrogen by adipose cells, which stimulates the growth of breast cells. There is some evidence that signaling molecules such as leptin and other adipocytokines may also act on these cells.

Insulin resistance may also contribute to the development of certain cancers. And the inflammation caused by obesity may also play an important role.

Of course, obesity is just one of many factors that affect risk of cancer. Whether an obese person develops a cancer will also depend on their genetic make-up and many environmental factors (e.g. whether or not they smoke). All these factors influence the control of the cell, and the wrong combination may drive them to uncontrolled multiplication.

Obesity and high blood pressure/heart disease

The links between obesity and blood pressure are equally complex, and again incompletely understood.

Both hormonal and nervous system mechanisms may be at work, and several hormone systems have found to be affected in obesity (particularly the renin-angiotensin-aldosterone system, a network of factors that control blood volume and hence blood pressure).

Obesity also interferes with kidney function, which may impact on blood pressure. The physical mass of fat tissue may also be detrimental to kidney function.

Again, obesity will be just one factor acting on this complex biological system.

Further reading

Rose DP, Komninou D, Stephenson GD.
Obesity, adipocytokines, and insulin resistance in breast cancer.
Obes Rev. 2004 Aug;5(3):153-65.

Yin N, Wang D, Zhang H, Yi X, Sun X, Shi B, Wu H, Wu G, Wang X, Shang Y.
Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin.
Cancer Res. 2004 Aug 15;64(16):5870-5.

Feigelson HS, Jonas CR, Teras LR, Thun MJ, Calle EE.
Weight gain, body mass index, hormone replacement therapy, and postmenopausal breast cancer in a large prospective study.
Cancer Epidemiol Biomarkers Prev. 2004 Feb;13(2):220-4.

Lahmann PH et al.
Body size and breast cancer risk: findings from the European Prospective Investigation into Cancer And Nutrition (EPIC).
Int J Cancer. 2004 Sep 20;111(5):762-71.

Wofford MR, Hall JE.
Pathophysiology and treatment of obesity hypertension.
Curr Pharm Des. 2004;10(29):3621-37.

Rahmouni K, Correia ML, Haynes WG, Mark AL.
Obesity-Associated Hypertension. New Insights Into Mechanisms.
Hypertension. 2004 Dec 6; [Epub ahead of print].