Regulation of BAT activity through central mechanisms

Current treatments of obesity and diabetes focus on increasing energy expenditure. The direct activation of brown fat (BAT) has been a major target in this strategy, as the tissue can dissipate substantial amounts of stored energy as heat (Cannon and Nedergaard 2004). However, a significant problem associated with this approach is the accompanying increase in body temperature (Warner and Mittag 2014), which is sensed by the brain. This may lead to a reduction in the sympathetic stimulation of BAT thermogensis, thus rendering this direct approach somewhat inefficient. Consequently, it seems more promising to activate the presympathetic neurons in the brain directly to overcome this feedback loop and induce a longlasting BAT thermogenesis compared to the situation found in the prolonged cold exposure. Unfortunately, however, the central circuits governing brown fat activation are incompletely understood (Nedergaard and Cannon 2014), since the presympathetic neurons in the brain do not have a common molecular marker, which hampers their identification or genetic manipulation.

In an attempt to identify hypothalamic neurons that play a role in the body's adaptation to cold (Miitag et al. 2013), we have established a retrograde tracing system from peripheral tissues using a GFP-expressing pseudorabies virus. The virus attached to the nerve terminals of the sympathetic neurons innervating the injection sites, infects these neurons, replicated and then transsynaptically jumps to the next higher-order neuron until it reaches the brain (Smith et al. 2000). Using this technique, we are able to identify the presympathetic neurons in the brain that are physically connected to the BAT (Mittag, unpublished), e.g. in the paraventricular nucleus of the hypothalamus (PVN). THese GFP positive cells can subsequently be analyzed or manipulated, as demonstrated in previous studies by our group (Wallis et al. 2010, Dudazy-Gralla et al. 2013).

The project will be divided in two parts, a neuroanatomical characterization of the presympathetic BAT-regulating neurons in the pVN (a) and subsequent in vivo studies aiming at activating these neurons to modulate thermogenesis (b).

Thesis topcis
-Molecular characterization of hypothalamic presympathetic neurons driving brown fat thermogenesis
-Central activation of brown fat thermogenesis by compounds targeting hypothalamic presympathetic neurons

Publications

Dore, R., Levata, L., Gachkar, S., Jöhren, O., Mittag, J., Lehnert, H., and Schulz, C.: The thermogenic effect of nesfatin-1 requires recruitment of the melanocortin system. J Endocrinol., vol. 235(2), pp. 111-122, 2017, doi: 10.1530/JOE-17-0151. Epub 2017 Aug 29 

Gachkar, S., Oelkrug, R., Martinez-Sanchez, N., Rial-Pensado, E., Warner, A., Hoefig, C. S., López, M., and Mittag, J.: 3-Iodothyronamine induces tail vasodilation through central action in male mice.Endocrinology, vol. 158(6), pp. 1977-1984, 2017, 10.1210/en.2016-1951