Home   >   Molecular Biology   >   Genes and Diseases

Obesity and Diabetes

 

Obesity

Obesity is characterized by excessive growth of adipocytes (fat cells), which are the primary site for energy storage in the form of triglycerides (fats). A triglyceride molecule consists of three fatty acid chains and a glycerol. When the body needs energy (e.g., during exercise), some hormones can activate a hormone-sensitive lipase that is present in large quantity at the fat cell membrane. The activated lipase then causes the breakdown of triglycerides, releasing free fatty acids for the production of ATP.

Many proteins are involved in the pathogenesis of obesity.  Among them, leptin plays the central role. Leptin is a 146 amino acid protein, encoded by the obesity (ob) gene. It is expressed mainly in adipocytes: the more fats in the cell, the more leptin molecules are produced. Leptin can counteract the buildup of fats by at least two different mechanisms: (1) regulating enzymes involved in the synthesis of fatty acids (reference 1, reference 2), and (2) inhibiting appetite.

The appetite is controlled by two types of neurons in the hypothalamus of the brain: NPY/AgRP neurons and POMC/CART neurons. Activation of the NPY/AgRP neurons releases NPY (neuropeptide Y) and AgRP (agouti-related protein), which stimulate appetite. Activation of the POMC/CART neurons releases a-MSH (a-melanocyte-stimulating hormone) and CART (cocaine and amphetamine-regulated transcript), which inhibits appetite. POMC (Pro-opiomelanocortin) is the precursor of a-MSH.

Leptin may circulate through the bloodstream to these neurons and act on its receptors, which relay the signal via the JAK/STAT pathway. In the NPY/AgRP neurons, leptin suppresses the expression of NPY and AgRP, while in the POMC/CART neurons, it enhances the expression of POMC and CART. Therefore, in both sets of neurons, leptin acts to reduce food intake, making the body leaner.

When the normal function of leptin was discovered, researchers thought that leptin might be used to treat obesity. Unfortunately, this is true only for very rare cases caused by defects in leptin or its production. For most obese people,  leptin and its production are normal. In fact, since the production of leptin increases with increasing fats, most obese people have high level of leptin, but it does not induce the expected responses.  This phenomenon is called leptin resistance, which could arise from certain defects in the leptin signaling cascade. Defective POMC has been found in a small number of obese people, but defects in leptin receptor, NPY or NPY receptor are rarely observed.

Recently, SOCS-3 (suppressor of cytokine signaling 3) has been demonstrated to play a key role in leptin resistance (reference). The leptin receptor belongs to the cytokine receptor family, which signals through the JAK/STAT pathway. SOCS proteins (SOCS-1 to 7) are the negative regulators of this signaling pathway. After cytokine stimulation, they are produced to avoid excessive stimulation. When leptin is injected into normal animals, the production of SOCS-3 increases. The signaling cascade is blocked by the binding of SOCS-3 to the leptin receptor (reference, Fig. 8). It has also been shown that older rats have less leptin sensitivity and higher SOCS-3 expression than younger rats (reference).

Protein tyrosine phosphatase 1B (PTP1B) is another negative regulator for the leptin signaling.  Its inhibitor could be an effective drug for treating obesity by increasing leptin sensitivity (reference). As discussed below, the type 2 diabetes is related to insulin resistance and leptin resistance. PTP1B acts as a negative regulator for both leptin and insulin signaling. Therefore, its inhibitor could be used for the two closely related diseases (reference 1, reference 2, reference 3).

Review Articles:

 

Diabetes

Diabetes is characterized by excess of glucose in the bloodstream, resulting from impairment in insulin release and/or insulin action. Normally, insulin is produced by the pancreas to move glucose from the bloodstream into muscle and other cells for the production of ATP. In diabetes patients, however, either the pancreas produces little or no insulin, or the insulin fails to act appropriately on the cells. Consequently, the glucose level increases in the blood.

Diabetes may be divided into three main types:

Type 1 diabetes
In type 1 diabetes, the immune system attacks the insulin-producing beta cells in the pancreas, which then produces little or no insulin. This type accounts for about 5 to 10 percent of diagnosed diabetes in the United States. It occurs mainly in children and young adults.

Type 2 diabetes
In type 2 diabetes, the insulin does not produce expected results - a phenomenon known as insulin resistance. This type accounts for more than 90 percent of diabetes. Most of its patients are over age 40 and overweight. 

Gestational diabetes
This type occurs during pregnancy. Although it usually disappears after delivery, the mother will more likely develop type 2 diabetes later in life.

Type 1 diabetes is also known as insulin-dependent diabetes because its patients need to take insulin daily. Type 2 diabetes is also called noninsulin-dependent diabetes, although insulin does play a critical role in this type of diabetes. MODY (maturity onset diabetes of the young) refers to the type 2 diabetes that occur in youngsters.

 

Insulin Release and Signaling

Insulin is stored in the secretory granules of beta cells. Glucose may enter beta cells via the glucose transporter (GLUT2) to produce ATP. The beta cell membrane contains ATP-sensitive potassium (KATP) channels which are open in the absence of ATP and closed upon ATP binding. The increase in cellular ATP concentration causes more KATP channels to close, resulting in membrane depolarization. This in turn opens the voltage-gated Ca2+ channels. The influx of Ca2+ stimulates the release of insulin from the secretory granules (see JBC, 2002, Fig. 1, and Diabetes, 2001, Fig.1).

The released insulin may circulate through the bloodstream and bind to its receptors on the surface of target cells. The insulin receptor is a receptor tyrosine kinase, which relays the signal via autophosphorylation and the phosphorylation of tyrosines on a variety of cellular proteins including insulin receptor substrate (IRS) (see JBC, 2002, Fig. 1). Four IRS proteins have been identified: IRS-1 to 4. The distinction between IRS-1 and IRS-2 has helped us understand the pathogenesis of type 2 diabetes (discussed below).

Review Article:

 

Type 1 Diabetes

Beta cells are destroyed by immune-mediated killing, either directly or indirectly.  In the direct process, autoantigens bind to MHC (major histocompatibility complex) class I molecules on the beta cell surface, resulting in the apoptosis of the beta cell. In the indirect process, autoantigens bind to MHC class II molecules on the antigen presenting cell (APC), resulting in the apoptosis of nearby beta cells (see JBC, 2002, Fig. 2). Three major autoantigens have been identified: GAD65 (an isoform of glutamic acid decarboxylase), IA-2 (a protein tyrosine phosphatase), and insulin. 

Review Articles:

 

Type 2 Diabetes

Insulin resistance, the early sign of type 2 diabetes, may be caused by the following mechanisms.

  1. Mutations of the genes involved in insulin signaling.
  2. Modifications of signaling proteins by glucose (reference).
  3. Inhibition of insulin signaling by lipids (reference).
  4. Excessive negative regulation of insulin signaling.

SOCS-3, which serves as a negative regulator for leptin signaling, is also a major negative regulator for insulin signaling. The mechanism, however, is different. SOCS-3 blocks insulin signaling by ubiquitin-mediated degradation of IRS-1 and IRS-2 (reference). In obese people, the leptin level is higher than normal, which tends to increase the SOCS-3 level.  Therefore, SOCS-3 provides an important link between diabetes and obesity.

Insulin resistance does not necessarily lead to diabetes (high glucose level), because beta cells can produce much more insulin to compensate for the resistance.  Diabetes results when the compensatory system fails. The IRS-1 knockout mice show insulin resistance, but rarely develop diabetes. By contrast, IRS-2 knockout mice develop both insulin resistance and diabetes. It is suggested that IRS-2 is involved in the compensatory production of insulin.

Review Articles