Type 2 diabetes (T2D) and metabolic syndrome (METS) are a major public health crisis affecting one in three
Americans. Though many treatments exist for these diseases, none target brain inflammation. This gap is
important because animal models show rapid induction of inflammation in metabolism regulating brain regions
such as the hypothalamus, particularly upon saturated fat exposure. Hypothalamic inflammation is a key cause
of chronic sympathetic nervous system (SNS) hyperactivity.
The SNS regulates most tissues through norepinephrine, a catecholamine neurotransmitter which binds ¿ and
¿ adrenergic receptors (¿-AR). In T2D and METS, sympathetic nerves are hyperactive in many tissues,
including white adipose tissue. In healthy adipose tissue, sympathetic nerves drive lipolysis: the release of free
fatty acids, and the exogenous stimulation of this circuit clinically promotes glucose homeostasis. However, in
the disease state, adipose tissue downregulates ¿-AR and exhibits impaired lipolysis in response to SNS input
(adipose catecholamine resistance). Chronically hyperactive sympathetic nerves could drive ¿-AR
downregulation, but no data directly show this at present, which hampers approaches to restoring endogenous
catecholamine sensitivity and improving glucose homeostasis.
In the present study, we ablate somatostatinergic (SST) neurons, an endogenous anti-inflammatory cellular
population, in the paraventricular region of hypothalamus. This intervention induces both hypothalamic
inflammation and visceral adipose catecholamine resistance, but no detailed studies of insulin/glucose
homeostasis or sympathetic nerve activity have been performed in this model under chow or high fat diet
feeding. Thus, our central hypothesis is that the ablation of hypothalamic SST neurons (SST-DTA) will
exacerbate HFD induced visceral adipose catecholamine resistance and glucose intolerance by
increasing hypothalamic inflammation and adipose sympathetic nerve activity. This hypothesis makes
the prediction that SST-DTA drives adipose catecholamine resistance by increasing sympathetic nerve activity.
Thus, our objective is to elucidate the consequences of ablating hypothalamic somatostatinergic neurons on
adipose sympathetic nerve activity, adipose catecholamine resistance, and glucose homeostasis, under
normal diet and HFD. This is in line with the mission of the NIDDK because it addresses important basic and
translational aspects of the development of METS and T2D. As a result of the proposed studies, we expect to
develop novel targets in the regulation of SNS activity which should prove useful in restoring adipose tissue
sensitivity to catecholamines. Importantly, somatostatin analogues are already FDA approved and can target
the hypothalamus, which suggests our data could support a drug repurposing approach to treating
hypothalamic inflammation and restoring adipose tissue lipolytic function. Completion of this proposal will also
contribute to my training as a physician scientist through the acquisition of key techniques and essential skills.