The laboratory of Robert V. Farese, Jr., asked whether insulin resistance is promoted specifically by fat accumulation in glycolytic (fast-twitch), rather than oxidative (slow-twitch), muscle. They tested their hypothesis in transgenic mice expressing an acyl-CoA:diacylglycerol acyltransferase (DGAT), which catalyzes triacylglycerol (TG) synthesis. Overexpression of DGAT2 in glycolytic muscle of young adult mice increased the content of TG and other lipids and caused reduced insulin signaling and glucose uptake in this tissue. These mice also exhibited an impaired whole-body glucose and insulin tolerance.

The researchers concluded that fat deposition specifically in glycolytic muscle is sufficient to impair insulin’s effects in this tissue. Insulin resistance resulting from this mechanism may contribute to the development of type 2 diabetes.

Levin MC, Monetti M, Watt MJ, Sajan MP, Stevens RD, Bain JR, Newgard CB, Farese RV Sr, Farese RV Jr (2007) Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic (type II) muscle. Am. J. Physiol. Endocrinol. Metab. 293:E1772–E1781.

SIRT4 Regulates Insulin Secretion
Although the sirtuins are known mostly as histone deacetylases and for their role in extending lifespan, this highly conserved family of proteins has many other functions.

Recently, the laboratory of Eric Verdin reported that one sirtuin, human SIRT4, is involved in the regulation of insulin secretion. The team localized SIRT4 to the mitochondria, the site of energy production for the cell. They also identified SIRT4 as a matrix protein and showed that it is cleaved to a specific length after it is imported into the mitochondria. SIRT4 was found in insulin-expressing cells in the islets of Langerhans of the pancreas. When SIRT4 was depleted in cultured insulin-producing cells, the amount of insulin secreted in response to glucose increased significantly.

These observations define a new role for mitochondrial SIRT4 in the regulation of insulin secretion and may represent another potential strategy for treating diabetes.

Ahuja N, Schwer B, Carobbio S, Waltregn D, North BJ, Castronovo V, Maechler P, Verdin E (2007) Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J. Biol. Chem. 282:33583–33592.

Defects in the Endosomal-Lysosomal Pathway Give Hints to Neurodegenerative Diseases
The cell has efficient systems for degrading and eliminating unwanted proteins. Such proteins may be derived from invading microbes, but most often they are misfolded or damaged proteins from the cell itself. By controlling the degradation and recycling of proteins, cellular pathways prevent the build-up of toxic proteins and protein fragments (peptides).

The endosomal-lysosomal pathway plays a particularly important role in this process. Defects in this pathway have been implicated in a number of neurodegenerative disorders. A key step in the regulation of transmembrane proteins occurs in a subset of late endosomal compartments known as multivesicular bodies (MVBs). MVB formation is controlled by a complex of proteins called ESCRT.

Recently, a team led by Gladstone investigator Fen-Biao Gao showed that mSnf7-2, a key protein component of ESCRT-III, is highly expressed in mammalian neurons. When mSnf7-2 was deleted from mature neurons, the neuronal branches that receive information from other cells (dendrites) retracted and the neurons died.

A link to neurodegenerative disease comes from the fact that mSnf7-2 binds to CHMP2B, another ESCRT-III subunit. A rare dominant mutation in CHMP2B is associated with a form of frontotemporal dementia called FTD3. Expression of the mutant CHMP2B protein causes dendritic retraction and ultimately neuronal loss. The Gao team found that the mutant form of CHMP2B bound mSnf7-2 more tightly than the normal wild-type form. In turn, the stronger binding caused mSnf7-2 to be sequestered in ubiquitin-positive late-endosomal vesicles in neurons and caused autophagosomes, vesicular structures for bulk degradation of cellular contents, to accumulate in neurons, both in cell culture and in live flies.

These findings indicate that dysfunction of ESCRT-III affects the autophagy pathway, which may have important implications for understanding FTD and other age-dependent neurodegenerative diseases.

Lee J-A, Beigneux A, Ahmad ST, Young SG, Gao F-B (2007) ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr. Biol. 17:1561–1567.

Finding the Way in Alzheimer's Disease
In Alzheimer's disease (AD), the ability to find one's way around is often impaired. However, the mechanisms underlying this impairment are unknown.

A team of Gladstone and UCSF physician-scientists led by Lennart Mucke and Bruce Miller explored navigation deficits in patients with AD or with mild cognitive impairment (MCI), a condition that often precedes AD and other neurodegenerative disorders. They tested 13 mild AD patients, 21 MCI cases and 24 controls on a route-learning task in the clinic, as well as in neurocognitive tests and imaging studies.

The patients and controls were taken on a route through the clinic and then asked to recall the route or landmarks on the route. Half of AD patients, 25% of MCI patients, and 10% of controls got lost. Patients that got lost on this task showed some shrinkage of key brain regions involved in navigation, particularly the right hippocampus and the parietal lobes. The ability of patients to remember locations on the map correlated well with right posterior hippocampal and parietal volumes. The ability to remember the sequence of objects seen on the route correlated with bilateral inferior frontal volumes.

This study showed that the navigational disabilities in AD and MCI involve specific impairments in spatial cognition that are not predictable based on standard neurocognitive tests. It also showed that navigational tests and radiological imaging studies can help identify the patients that are at the greatest risk of getting lost.

deIpolyi AR, Rankin KP, Mucke L, Miller BL, Gorno-Tempini ML (2007) Spatial cognition and the human navigation network in AD and MCI. Neurology 69:986–997.