Signalling pathways regulating adipose tissue thermogenesis

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Discoveries over the past decade have changed the way we understand fat. More than just a passive energy store, we now know that fat can regulate metabolism, and, intriguingly, can be a major source of energy expenditure through the process of generating heat, known as thermogenesis. Brown fat is now recognized as a unique type of fat, while beige fat is found within classic white fat but has some similarities to brown fat. Notably, brown and beige fat can be stimulated to increase thermogenesis in humans and mice, but how this process is regulated remains unclear and is the subject of this work.******The long term objective of this research program is to identify pathways regulating thermogenesis in fat. Our preliminary data suggest that a protein called caspase 8 could be important in adipose tissue and thermogenesis. Thus, our short term goals are 1) to determine how caspase 8 regulates thermogenesis, 2) identify the role of caspase 8 in regulating inflammation, and 3) establish the role of inflammatory signaling in adipose tissue thermogenesis.******To study the role of signaling pathways in whole body physiology and heat production, we will use knockout mice. To study the isolated effects of signaling pathways in fat, we will use fat cells grown in cell culture. We will knockout signaling proteins in mice and treat cultured adipocyte cells with inhibitors to determine the role of different signaling pathways in metabolism.******To determine the role of caspase 8 in thermogenesis, we will use mice with caspase 8 knocked out only in fat tissue. Animals will be fed a standard chow diet or a Western-style high fat diet to study what happens under basal conditions and conditions of caloric excess. Animals will also be housed at comfortable or cold temperatures to analyze measures of metabolism and heat production under both minimal and increased stimulation. ******To identify whether caspase 8 regulates inflammatory signaling in fat, we will measure activation of inflammatory signaling in fat from these fat-specific caspase 8 knockout mice. We will also study mice with knockout of caspase 8 but activation of inflammatory signaling in fat, to determine if caspase 8 regulates metabolism by controlling inflammation.******Finally, we will also study inflammatory signaling and mice or cells with activated inflammation to determine if this regulates metabolism. Animals will be fed chow or high fat diet, and housed at comfortable or cold temperature, to be assessed for weight gain, energy expenditure and core body temperature. ******This work will establish new roles for the fundamental caspase 8 and inflammatory signaling pathways in adipose tissue biology and thermogenesis, and identify interactions between these pathways. This work will form the basis for the next major step in understanding the intriguing phenomenon of adipose tissue thermogenesis in whole body physiology.