Allison Xu, PhD

Professor
Diabetes Center
+1 415 476-2807

Research in our laboratory focuses on understanding leptin and the central melanocortin system in regulation of feeding, body weight, hepatic lipid and glucose metabolism. Highlights of our recent research are described below.

Hypothalamic leptin-melanocortin pathway in regulation of hepatic lipid metabolism

Our laboratory has recently delineated a novel neuroendocrine circuit in regulation of non-alcoholic fatty liver under physiologic conditions such as starvation and diet-induced obesity. We show that leptin acts in the brain to regulate autonomic activity and suppress triglyceride content in the liver. Induction of cellular leptin resistance in the brain, a hallmark feature of obesity, results in hepatic steatosis independent of hyperphagia and obesity. We further show that modulation of leptin levels during fasting is important for starvation-induced hepatic steatosis, and that this effect is mediated by hypothalamic Agouti-related protein (AGRP). AGRP modulates hepatic sympathetic activity, activates hepatic expression of acyl CoA:diacylglycerol acyltransferase-2 (Dgat2), and increases triglyceride levels. AGRP deficiency, despite having no effects on feeding and body adiposity in the fed state, attenuates hepatic steatosis and impairs energy release from the liver during prolonged food deprivation. These results demonstrate that AGRP neuropeptide plays an indispensible role in regulation of hepatic lipid synthesis, a function that is uncoupled from feeding regulation. Our research further shows that AGRP innervation onto selective neuronal targets increases in diet-induced obesity, and that inhibition of AGRP expression protects mice from high-fat diet (HFD)-induced hepatic steatosis. These results raise the possibility that this pathway may also contribute to obesity-associated hepatic steatosis.

Neurogenesis in the adult hypothalamus as a compensatory regulatory mechanism to restore energy balance

Maintenance of energy balance in an ever-changing environment requires the brain to cope with a variety of environmental and metabolic insults. The ability to develop compensatory mechanisms to escape severe energy imbalance is essential for survival. This compensatory regulation of energy balance is frequently observed in rodent models with various genetic manipulations, but its underlying mechanisms remain largely unknown. Hypothalamus in the adulthood possesses low levels of neurogenic activity, although abundant neural progenitor cells are present in the adult hypothalamus and they exhibit stem cell properties and differentiate into neuropeptide-expressing neurons in vitro. This suggests that adult hypothalamus, like many other regions of the adult brain, lacks a permissive microenvironment for neurogenesis. We have shown that hypothalamic neurons important for energy homeostasis can be regenerated in adult hypothalamus in response to progressive degeneration of AgRP neurons, and that inhibition of cell proliferation in the mutant brain affects feeding and adiposity.

Adaptive mechanisms that underlie increased body adiposity associated with aging or diet-induced obesity

We recently show that AgRP neurons make up close to 70% of cells outside the blood-brain barrier (BBB) in the mediobasal hypothalamus, whereas neurons expressing Proopiomelanocortin (POMC) make up about 10%. AgRP neurons precede POMC neurons in developing diet-induced cellular leptin resistance, and dynamic increase of SOCS3 in AgRP neurons after acute consumption of fat-rich diet may serve as an initiating event in diet-induced hypothalamic leptin resistance. Thus, modulation of SOCS3 expression in AgRP neurons may play a dynamic role in metabolic fine tuning in response to short-term changes of nutritional status. Our results further suggest that AgRP neurons are able to sense small changes in plasma metabolic signals, allowing them to serve as first-line responders to fluctuation of energy intake. Intriguingly, we have recently shown that AGRP innervation onto POMC and other hypothalamic neurons increases markedly with age. This is associated with progressive increase in inhibitory postsynaptic currents and decreased POMC neuronal firing rate. Neuronal activity is attenuated in POMC neurons that receive high density AGRP puncta. The age-associated increase in AGRP innervation is accelerated by chronic consumption of a fat-rich diet. These high-density AGRP inputs correlate with leptin levels in wild type mice and are nearly absent in mice lacking leptin. Together our study suggests that modulation of hypothalamic AGRP innervation may constitute one mechanism to counter the effects of the age-associated rise in leptin levels, thus sustaining body weight and fat mass at elevated levels in adulthood.

Primary Thematic Area: 
Tissue / Organ Biology & Endocrinology
Secondary Thematic Area: 
Neurobiology
Research Summary: 
Hypothalamic regulation of appetite, body weight, hepatic lipid and glucose metabolism

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