Writing in The Journal of Clinical Investigation (JCI), the team behind the research noted that he brain plays a central role in regulating appetite and whole-body metabolism, adding that the PPAR-gamma protein is known to be important in the brain's control of food intake and body weight but the identity of the neurons regulating this process have so far been unclear.
The new findings suggest that PPAR-gamma activity in a type of neuron known as pro-opiomelanocortin (POMC) neurons is essential in controlling the response to high-fat diet - with data from mice showing that when the effects of the nuclear receptor PPAR-gamma in POMC cells are blocked, animals consume less and become resistant to a high-fat diet.
As a result, the Yale School of Medicine led research team suggest that preventing weight gain, obesity, and ultimately diabetes could be as simple as keeping these nuclear receptors from being activated.
“These animals ate fat and sugar, and did not gain weight, while their control littermates gained weight on the same diet,” revealed Professor Sabrina Diano of Yale, who led the research.
“We showed that the PPAR-gamma receptor in neurons that produce POMC could control responses to a high-fat diet without resulting in obesity.”
Diano and her team studied mice that were genetically engineered to delete the PPARgamma receptor from POMC neurons in order to test the effects of blocking this signal on metabolism and obesity in response to a high-fat, high-sugar diet.
POMC neurons are found in the hypothalamus and regulate food intake. When activated, these neurons cause a feeling of fullness and curb appetite. PPAR-gamma regulates the activation of these neurons.
The team found that mice lacking PPAR-gamma specifically in POMC neurons gained less weight, were more active, and had improved glucose metabolism when fed a high-fat diet.
“When we blocked PPAR-gamma in these hypothalamic cells, we found an increased level of free radical formation in POMC neurons, and they were more active,” said Diano.
Moreover, animals without PPAR-gamma in POMC neurons did not gain weight when given PPAR-gamma activators, said the team - adding that this indicates that PPAR-gamma expression in POMC neurons regulates whole-body energy balance.
"These observations give further support to the notion that appropriate cellular biological adaptations in hypothalamic neurons, including ROS control, represent crucial components in leptin sensitivity and resistance and related metabolic and glucose control," said the team.
Diabetes, drugs, and unwanted side effects
Diano and her team also suggested that the findings may also shed light on why PPAR-gamma activators, which are used clinically to increase insulin sensitivity in patients with type 2 diabetes, have a side effect of promoting weight gain.
Indeed, the team noted that PPAR-gamma is a target of thiazolidinedione (TZD), a class of drugs used to treat type 2 diabetes. Such drugs are used to lower blood-glucose levels, however patients gain weight on these medications.
“Our study suggests that the increased weight gain in diabetic patients treated with TZD could be due to the effect of this drug in the brain, therefore, targeting peripheral PPAR-gamma to treat type 2 diabetes should be done by developing TZD compounds that can’t penetrate the brain,” said Diano.
“We could keep the benefits of TZD without the side-effects of weight gain. Our next step is to test this theory in diabetes mouse models.”
Source: The Journal of Clinical Investigation
Published online ahead of print, doi: 10.1172/JCI76220
"PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding"
Authors: Lihong Long, Chitoku Toda, et al